Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein superfamily together with (...) albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. In reviewing (...) this field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

Saethre‐Chotzen syndrome (SCS), a human autosomal dominant condition with limb defects and craniosynostosis, is caused by haploinsufficiency of TWIST1, a basic helix–loop–helix (bHLH) transcription factor. Until recently, the molecular pathogenesis of the limb defects in SCS has not been well understood. Now, Firulli et al.1 show in mouse and chick that ectopic expression of a related bHLH protein, Hand2, results in phenocopies of the limb defects caused by Twist1 loss‐of‐function mutations. These two proteins interact in a dosage‐dependent antagonistic manner, and (...) both can be regulated through phosphorylation at conserved helix I amino acid residues. These findings provide an important link between the misregulation of Twist1 dimerization and the limb phenotypes observed in SCS. BioEssays 27:1102–1106, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and (...) BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH2/NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH2, e.g., during FAO or glycerol‐3‐phosphate shuttle use. Here it is proposed that the Q‐cycle of Complex III contributes to enhanced ROS formation going (...) from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q‐cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS‐induced uncoupling. (shrink)

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of (...) SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

We highlight the various domains of the flavivirus virulence factor NS1 and speculate on potential implications of the NS1 3D structure in understanding its role in flavivirus pathogenesis. Flavivirus non‐structural protein 1 (NS1) is a virulence factor with dual functions in genome replication and immune evasion. Crystal structures of NS1, combined with reconstructions from electron microscopy (EM), provide insight into the architecture of dimeric NS1 on cell membranes and the assembly of a secreted hexameric NS1‐lipid complex found in patient sera. (...) Three structural domains of NS1 likely have distinct roles in membrane association, replication complex assembly, and immune system avoidance. A conserved hydrophobic inner face is sequestered either on the membrane or in the interior of the secreted hexamer and contains regions implicated in viral replication. The exposed variable outer face is presented to cellular and secreted components of the immune system in infected patients and contains candidate regions for immune system modulation. We anticipate that knowledge of the distinct NS1 domains and assembly will lead to advances in elucidating virus‐host interactions mediated through NS1 and in dissecting the role of NS1 in viral genome replication. (shrink)

Platelet‐derived growth factor (PDGF) was originally identified in platelets and in serum as a mitogen for fibroblasts, smooth muscle cells (SMC) and glia cells in culture. PDGF has since expanded to a family of dimers of at least four gene products, whose biological actions are mediated through two receptor tyrosine kinases, PDGFRs. The present review summarizes and discusses the biological functions of PDGFs and PDGFRs in developmental processes, mainly as revealed through genetic analysis in mice. Such studies have demonstrated multiple (...) critical roles of PDGFs and PDGFRs in embryonic and postnatal development. PDGFs seem to act upon specific populations of progenitor cells that give rise to several different cell types with distinct functions in a variety of developmental processes. Analogies are seen between the cell functions and the developmental processes controlled by PDGFs. This suggests that ancestral PDGF and PDGFR expression patterns and functions may have been iterated in related sets of morphogenetic processes in the course of evolution. BioEssays 23:494–507, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Biofilms can be viewed as tissue‐like structures in which microorganisms are organized in a spatial and functional sophisticated manner. Biofilm formation requires the orchestration of a highly integrated network of regulatory proteins to establish cell differentiation and production of a complex extracellular matrix. Here, we discuss the role of the essential Bacillus subtilis biofilm activator RemA. Despite intense research on biofilms, RemA is a largely underappreciated regulatory protein. RemA forms donut‐shaped octamers with the potential to assemble into dimeric superstructures. The (...) presumed DNA‐binding mode suggests that RemA organizes its target DNA into nucleosome‐like structures, which are the basis for its role as transcriptional activator. We discuss how RemA affects gene expression in the context of biofilm formation, and its regulatory interplay with established components of the biofilm regulatory network, such as SinR, SinI, SlrR, and SlrA. We emphasize the additional role of RemA played in nitrogen metabolism and osmotic‐stress adjustment. (shrink)

İSNAD, sosyal ve beşeri bilimler alanında hazırlanan çalışmalarda kullanılmak üzere Türkiye merkezli olarak geliştirilen akademik yazım ve kaynak gösterme sistemidir. “Kaynak gösterme”, bilginin bilimselliğinin bir gereği olduğu kadar fikrî mülkiyet ve telif haklarına saygının da bir gereğidir. İstifade edilen bir kaynağın araştırmada belirtilmemesi yayın etiği suçudur (intihal / plagiarism). Bu sebeple ortaya konulan bilimsel bir çalışmanın kaynakları, başka araştırmacılar tarafından tekrar ulaşılabilir ve kontrol edilebilir olacak şekilde bibliyografik bileşenleri ile doğru ve eksiksiz olarak yazılmak durumundadır. İSNAD atıf sistemi ise Türkiye (...) merkezli olarak Antropoloji, Arkeoloji ve Sanat Tarihi, Coğrafya, Dil ve Edebiyat, Eğitim, Felsefe, Halkbilimi, Hukuk, İktisadi ve İdari Bilimler, İlahiyat, Psikoloji, Sanat, Sosyal Hizmetler, Sosyoloji ve Tarih gibi sosyal ve beşeri bilimler alanında görülen atıf ve kaynak gösterme gereksinimlerinin giderilmesi amacıyla geliştirilmiştir.İSNAD atıf sistemi; akademik bir yazının başlığının nasıl belirleneceği, özetinin hangi bilgileri içermesi gerektiği, anahtar kavramların nasıl seçileceği, başlıklandırma formatının nasıl olması gerektiği, içerdiği tablo ve şekillerin nasıl oluşturulacağı, çalışmada kullanılan Arapça, Farsça, İngilizce ve diğer eser adlarının ve müellif isimlerinin nasıl yazılacağı, tarih ve yüzyılların hangi şekilde gösterileceği, yayın etiği kapsamında nelere dikkat edilmesi gerektiği, istifade edilen kaynak eserden dolaylı veya doğrudan nasıl alıntı yapılacağı, atıf yapılan kaynakların metin içinde veya dipnotta nasıl yazılacağı ve kaynakçanın nasıl oluşturulacağı gibi akademik yazımla ilgili bilinmesi ve uygulanması gerekli tüm kuralları içermektedir.Sözlükte “dayanmak, yaslanmak, itimat etmek” manasındaki “sened” kökünden türeyen isnad, “temellendirmek, dayamak; sözü söyleyenine kadar ulaştırmak, bir sözün, bir rivayetin geliş yolunu haber vermek, ilk kaynağa kadar götürmek” anlamlarına gelmektedir. “Sözünün senedi nedir?” örneğinde olduğu gibi sözün kaynağını sorgulamak ve belirtmek için kullanılmaktadır. Bu anlamda isnad, akademik yazımda atıf veya alıntı yapılan kaynağı belirtmek için geliştirilen atıf sistemine, Türkiye merkezli yayın yapan ilahiyat alan dergilerinde görev üstlenen editörlerin çoğunluğunun (%70,4) kararı ile ad olarak seçilmiştir.İSNAD atıf sistemi, 2017-2018 yıllarında “İlahiyat Atıf Sistemi” olarak geliştirildi ve ilk versiyonu 12/03/2018 tarihinde matbu ve online olarak yayınlanarak ücretsiz olarak kullanıma sunuldu. Sistemin Türkiye’de ve Türk Cumhuriyetlerinde ilahiyat alan dergileri arasında ilgi görmesi ve ilahiyat alanı dışında da kullanımına dair talepler gelmesi üzerine İSNAD’ın ikinci versiyonu, tüm sosyal bilimler alanında kullanılabilecek şekilde geliştirildi ve Eylül 2018 itibari ile hizmete sunuldu. İSNAD artık sosyal ve beşeri bilimlerin tüm alanlarında kullanılabilmektedir.İSNAD atıf sistemi, Dr. Abdullah Demir tarafından Sivas Cumhuriyet Üniversitesi Rektörlüğü’nce desteklenen RGD-015 numaralı “Ulusal İlahiyat Atıf Dizini Projesi” kapsamında, Sivas Cumhuriyet Üniversitesi Dini İlimler Uygulama ve Araştırma Merkezi (DİMER) bünyesinde, akademik yayıncılık alanında uzman öğretim üyelerinin ve hakemli dergi editörlerinin görüş, öneri ve değerlendirmeleri alınarak geliştirildi. Yaygın atıf biçimlerinden APA, Amerika Psikoloji Derneği (American Psychology Association) ve Chicago ise Modern Diller Derneği (Modern Languages Association) tarafından geliştirilerek satışa sunulmuştur.İSNAD; Türkiye merkezli olarak geliştirilen, kullanıma sunulduğu 12/03/2018 tarihinden kısa bir süre sonra hakemli akademik dergi ve kitap yayıncıları ile Fakülte Dekanlıkları (mezuniyet tezlerinin yazımında) ve Sosyal Bilimler Enstitüsü Müdürlüklerince (Yüksek Lisans ve doktora tezlerinin yazımında) kullanımı benimsenen, Web of Science / Clarivate Analytics, TÜBİTAK TR Dizin ve TÜBİTAK DergiPark gibi akademik yayıncılıkla ilgili indeks ve dergi platformlarınca kaynak gösterme biçimlerinden biri olarak sistem entegrasyonu yapılan, Zotero, Mendeley ve EndNote gibi dünya çapında kullanılan kütüphane ve referans düzenleme yazılımlarına uygun şablonları hazırlanan ve ücretsiz olarak kullanıma sunulan ilk ve tek yerli-milli kaynak gösterme sistemidir ve bu açıdan oldukça önem arz etmektedir. Türkçe’nin bir bilim dili haline gelmesi hedefleniyorsa, bu hedefe ulaşmada, Türkçe olarak hazırlanan bir bilimsel yazım ve kaynak gösterme sisteminin bulunması da bir zorunluluktur. Ortaöğretim ve üniversite öğrencilerinin Türkçe olarak hazırlanan ve ücretsiz olarak kullanıma sunulan İSNAD atıf sistemini öğrenmeleri ve kullanmaları, aslı İngilizce olan ve satın alma imkanı da elde edemeyecekleri sistemleri öğrenmelerine kıyasla daha elverişlidir ve kolaydır. Türkçe konuşan ülkelerin bilim insanlarının bildiri, makale, kitap, proje ve benzeri bilimsel çalışmalarını İSNAD atıf sistemini kullanarak hazırlamaları, Türkçenin ortak bir bilim dili olarak güçlenmesine katkı sağlayacaktır. İSNAD atıf sistemi ile Türkiye’de ve Türki Cumhuriyetlerde; Antropoloji, Arkeoloji, Coğrafya, Dil ve Edebiyat, Felsefe, Halkbilimi, Hukuk, İktisadi ve İdari Bilimler, İlahiyat, Müzik, Psikoloji, Sanat Tarihi, Sosyal Hizmetler, Sosyoloji ve Tarih gibi sosyal ve beşeri bilimler alanında hazırlanan yayınlarda ortak bir atıf sisteminin kullanımını sağlamak hedeflenmektedir. İSNAD atıf sisteminin kullanımı, Türkçe konuşan ülkelerde sosyal ve beşeri bilimler alanında kaynak göstermede standartlaşmayı sağlayarak atıf ve etki değeri tespitine olanak sağlayacak ve Türk dünyası arasında bilimsel iletişimi kolaylaştıracaktır.İSNAD atıf sistemi, sosyal ve beşeri bilimler alanında araştırma yapan ve yazı kaleme alan öğrenciler, akademisyenler ve yazarlar ile bu alanda yayın yapan kurum ve kuruluşların hizmetine sunulmuştur. Sosyal bilimler alanında yayın yapan birçok dergi İSNAD atıf sistemini kullanmaya başlamıştır. Lisans mezuniyet tezi, yüksek lisans tezi ve doktora tezlerinin yazımında İSNAD atıf sisteminin kullanılmasını öngören ve bunu tez yazım kılavuzlarına dahil eden üniversitelerin sayısı artmaktadır. Ayrıca ulusal ve uluslararası sempozyum ve kongre düzenleyen birçok kurum ve kuruluş, katılımcıların bildirilerini İSNAD atıf sistemine uygun olarak hazırlamalarını talep etmeye başlamıştır. Ücretsiz olarak kullanıma sunulan bu sistem, kullanıcı dostu arayüzü ve kaynak gösterme yazılım eklentileri ile hızla kabul görmekte ve benimsenmektedir. Öğrenciler, yazarlar, araştırmacılar ve akademisyenler; İSNAD’ın EndNote, Zotero ve Mendeley gibi kaynak gösterme yazılım eklentileri sayesinde daha kolay, daha hızlı ve hatasız olarak “atıf ve kaynak gösterme” işlemlerini yapabilmektedirler. Bu sisteminin Türkiye ve Türk Cumhuriyetlerinde kullanımı yaygınlaşmaya devam etmektedir. www.isnadsistemi.org. (shrink)

The subcellular location and function of many proteins are regulated by nuclear–cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ‐line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair protein (...) function and nuclear accumulation. BRCA1 and BARD1 shuttle between the nucleus and cytoplasm; however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1–BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications. BioEssays 27:884–893, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Transcriptional regulation is coupled with numerous intracellular signaling processes often mediated by second messengers. Now, growing evidence points to the importance of Ca2+, one of the most versatile second messengers, in activating or inhibiting gene transcription through actions frequently mediated by members of the EF‐hand superfamily of Ca2+‐binding proteins. Calmodulin and calcineurin, representative members of this EF‐hand superfamily, indirectly regulate transcription through phosphorylation/dephosphorylation of transcription factors in response to a Ca2+ increase in the cell. Recently, a novel EF‐hand Ca2+‐binding protein (...) called DREAM has been found to interact with regulatory sequences of DNA, thereby acting as a direct regulator of transcription. Finally, S100B, a dimeric EF‐hand Ca2+‐binding protein, interacts with the tumor suppressor p53 and controls its transcriptional activity. In light of the structural studies reported to date, this review provides an overview of the structural basis of EF‐hand Ca2+‐binding proteins linked with transcriptional regulation. BioEssays 24:625–636, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The c‐myc proto‐oncogene is believed to be involved in the regulation of cell growth and differentiation. Deregulation of this gene, resulting in an inappropriate increase of gene product, can contribute to cancer formation. One of the ways in which the expression of the c‐myc gene can be deregulated is by the stabilization of the labile c‐myc mRNA. The rapid degradation of the c‐myc transcript appears to be mediated by at least two distinct regions in the mRNA. One lies in the (...) 3' untranslated region, and presumably consists of (A+U)‐rich sequences. The other lies in the C‐terminal part of the coding region and colocalizes with sequences encoding protein‐dimerization motifs. The exact mechanism by which the destabilizing elements function is not yet clear. Shortening of the poly(A) tail of the c‐myc message appears to precede degradation of the transcript. When translation is blocked, this shortening is slowed down and the mRNA is stabilized. This suggests that deadenylation is required before degradation of the mRNA body can take place. (shrink)

The laser scanning confocal microscope (LSCM)LSCM: laser scanning confocal microscope; FISH: fluorescence in situ hybridisation; DiO6: 3,3′‐dihexyloxacarbocyanine iodide; NBD‐ceramide: 6‐((N‐(7‐nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)amino)‐caproyl)sphingosine; DiO: 3,3′‐dioctadecyloxacarbocyanine perchlorate; DiI: 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate; CCD: charge‐coupled device; DIC: differential interference contrast; FURA2: (‐(2‐(5‐carboxyoxazol‐2‐yl)‐6‐aminobenzofuran‐5‐oxy)‐2‐)2′‐amino‐5′‐methylphenoxy)‐ethane‐N,N,N′,N′‐ tetraacetic acid, sodium salt);BCECF: 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6‐)‐carboxyfluorescein;fluo‐3: 1‐(2‐amino‐5‐(2,7‐dichloro‐6‐hydroxy‐3‐oxo‐3H‐xanthen‐9‐yl)‐2‐(2′amino‐5′‐methylphenoxy)‐ethane‐N,N, N′,N′,‐tetraacetic acid, ammonium salt; DAPI: 4′,6‐diamidino‐2‐phenylindole, dihydrochloride; PET: positron emission tomogrophy; CT: computer‐assisted tomogrophy; CiD: cubitus interruptus dominus; MRC: Medical Research Council; TOTO‐1: benzothiazolium‐4‐quinolinium dimer; YOYO‐1: benzoxazolium‐4‐quinolinium dimer; ex.: excitation wavelength; em.: emission wavelength. is now established as an invaluable tool in (...) developmental biology for improved light microscope imaging of fluorescently labelled eggs, embryos and developing tissues. The universal application of the LSCM in biomedical research has stimulated improvements to the microscopes themselves and the synthesis of novel probes for imaging biological structures and physiological processes. Moreover the ability of the LSCM to produce an optical series in perfect register has made computer 3‐D reconstruction and analysis of light microscope images a practical option. (shrink)

Florentin Smarandache është një nga shkrimtarët më të talentuar në letërsinë rumune të diasporës. Dashuria e saj për librin ripërtërihet gjithmonë, duke arrdhur tani para lexuesve tanë me një libër të ri të ilustruar dhe të destinuar për lexuesit më të vegjël. Kjo është një befasi e re me disa tregime të bukura për shijen e fëmijëve të ditëve tona. Florentin Smarandache është një adhurues i leximit, një krijesë frymëzimesh të zjarrta për të cilin leximi është bërë një mënyrë e (...) vërtetë jetese, një lloj zgjatje e qenies së tij. Nuk e dimë saktësisht se kur i imagjinonte krijimet e para, por e dimë se ai mësoi të lexonte e të shkruante, me hirin hyjnor, përpara se të hynte në shkollë. Ai ka qenë I magjepsur që atëherë nga fuqia e fjalës, nga mënyra se si u bashkuan për të formuar fjalë dhe nga kuptimet dhe fuqia që mund të sillnin. Pastaj e di se ai mezi priste të huazonte libra nga biblioteka e shkollës dhe se hyri në atë dhomë që dukej e madhe me shumë emocion. Florentini lexonte libër pas libri, duke dashur gjithmonë më shumë, duke pasur parasysh se nuk kalonte mjaftueshëm kohë në shoqërinë e miqve më të mirë që kishte pasur ndonjëherë. Në momentin që hap një libër të ilustruar për fëmijë, hyn në një botë tjetër, ndryshe nga ajo e të rriturve. Jeni të zhytur nga bukuria e botëve të pikturuara me ngjyra nga krijues dhe ilustrues të talentuar, pastaj takoni heronj fantastikë me të cilët gjithçka është e mundur. Autori gjithmonë i ka dashur fëmijët, poezitë dhe tregimet për të vegjlit, sepse librat për fëmijë e kanë magjepsur. Nëse e pyesni veten se si ka nisur të shkruajë, për krimtarin Florentin Smarandache, historia është shumë e bukur. Kur fëmijët filluan të shkonin në shkollë, kishin nevojë për përralla dhe poezi për raste të ndryshme, për vjeshtë, për Vitin e Ri, për dimër, për pranverë, dhe kështu ai filloi të shkruante poezi në letër, ku fëmijët ishin lexuesit dhe kritikët e saj të parë letrarë. (shrink)

MutL family proteins contain an N‐terminal ATPase domain (NTD), an unstructured interdomain linker, and a C‐terminal domain (CTD), which mediates constitutive dimerization between subunits and often contains an endonuclease active site. Most MutL homologs direct strand‐specific DNA mismatch repair by cleaving the error‐containing daughter DNA strand. The strand cleavage reaction is poorly understood; however, the structure of the endonuclease active site is consistent with a two‐ or three‐metal ion cleavage mechanism. A motif required for this endonuclease activity is present (...) in the unstructured linker of Mlh1 and is conserved in all eukaryotic Mlh1 proteins, except those from metamonads, which also lack the almost absolutely conserved Mlh1 C‐terminal phenylalanine‐glutamate‐arginine‐cysteine (FERC) sequence. We hypothesize that the cysteine in the FERC sequence is autoinhibitory, as it sequesters the active site. We further hypothesize that the evolutionary co‐occurrence of the conserved linker motif with the FERC sequence indicates a functional interaction, possibly by linker motif‐mediated displacement of the inhibitory cysteine. This role is consistent with available data for interactions between the linker motif with DNA and the CTDs in the vicinity of the active site. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite of (...) the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

It was initially believed that G‐protein‐coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G‐proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G‐proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the classical G‐protein‐coupled second (...) messenger pathways. Notably, several of these mechanisms connect mGluR‐mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C‐termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C‐termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development. BioEssays 29: 60–73, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Almost 40 years since the discovery of microtubule dynamic instability, the molecular mechanisms underlying microtubule dynamics remain an area of intense research interest. The “standard model” of microtubule dynamics implicates a “cap” of GTP‐bound tubulin dimers at the growing microtubule end as the main determinant of microtubule stability. Loss of the GTP‐cap leads to microtubule “catastrophe,” a switch‐like transition from microtubule growth to shrinkage. However, recent studies, using biochemical in vitro reconstitution, cryo‐EM, and computational modeling approaches, challenge the simple GTP‐cap (...) model. Instead, a new perspective on the mechanisms of microtubule dynamics is emerging. In this view, highly dynamic transitions between different structural conformations of the growing microtubule end – which may or may not be directly linked to the nucleotide content at the microtubule end – ultimately drive microtubule catastrophe. (shrink)

We apply molecular code theory to a rule-based model of the human inner kinetochore and study how complex formation in general can give rise to molecular codes. We analyze 105 reaction networks generated from the rule-based inner kinetochore model in two variants: with and without dissociation of complexes. Interestingly, we found codes only when some but not all complexes are allowed to dissociate. We show that this is due to the fact that in the kinetochore model proteins can only bind (...) at kinetochores by attaching to already attached proteins and cannot form complexes in free solution. Using a generalized linear mixed model we study which centromere protein can take which role in a molecular code . By this, associations between CENPs and code roles are found. We observed that CenpA is a major risk factor while CenpQ is a major protection factor . Finally we show, using an abstract model of copolymer formation, that molecular codes can also be realized solely by the formation of stable complexes, which do not dissociate. For example, with particular dimers as context a molecular code mapping from two different monomers to two particular trimers can be realized just by non-selective complex formation. We conclude that the formation of protein complexes can be utilized by the cell to implement molecular codes. Living cells thus facilitate a subsystem allowing for an enormous flexibility in the realization of mappings, which can be used for specific regulatory processes, e.g. via the context of a mapping. (shrink)

Plant‐specific NAC transcription factors (TFs) evolve during the transition from aquatic to terrestrial plant life and are amplified to become one of the biggest TF families. This is because they regulate genes involved in water conductance and cell support. They also control flower and fruit formation. The review presented here focuses on various properties, regulatory intricacies, and developmental roles of NAC family members. Processes controlled by NACs depend majorly on their transcriptional properties. NACs can function as both activators and/or repressors. (...) Additionally, their homo/hetero dimerization abilities can also affect DNA binding and activation properties. The active protein levels are dependent on the regulatory cascades. Because NACs regulate both development and stress responses in plants, in‐depth knowledge about them has the potential to help guide future crop improvement studies. (shrink)

The formation of DNA photoproducts by ultraviolet (UV) light is responsible for induction of mutations and development of skin cancer. To understand UV mutagenesis, it is important to know the mechanisms of formation and repair of these lesions. Cyclobutane pyrimidine dimers and (6–4)photoproducts are the two major classes of UV‐induced DNA lesions. Their distribution along DNA sequences in vivo is strongly influenced by nucleosomes and other DNA binding proteins. Repair of UV photoproducts is dependent on the transcriptional status of the (...) sequences to be repaired and on the chromatin environment. Sensitive techniques are now available to study repair of UV damage at the level of nucleotide resolution in mammalian cells. With the aid of in vitro systems, the entire nucleotide excision repair process has been reconstituted from purified protein components with naked DNA as a substrate. Future work will focus on the development of in vitro assays for transcription‐coupled repair and repair in chromatin. (shrink)

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, crosslinks two receptor (...) sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

The mechanisms by which most receptor protein‐tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in which genes (...) encoding RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Under the putative influence of dietary selection pressure, the subcellular distribution of alanine:glyoxylate aminotransferase 1 (AGT) has changed on many occasions during the evolution of mammals. Depending on the particular species, AGT can be found either in peroxisomes or mitochondria, or in both peroxisomes and mitochondria. This variable localization depends on the differential expression of N‐terminal mitochondrial and C‐terminal peroxisomal targeting sequences by the use of alternative transcription and translation initiation sites. AGT is peroxisomal in most humans, but it is (...) mistargeted to the mitochondria in a subset of patients suffering from the rare herediatry disease primary hyperoxaluria type 1. Mistargeting is due to the unlikely combination of a normally occurring polymorphism that generates a functionally weak mitochondrial targeting sequence and a disease‐specific mutation which, in combination with the polymorphism, inhibits AGT dimerization. The mechanisms by which AGT can be targeted differentially to peroxisomes and/or mitochondria highlight the different molecular requirements for protein import into these two organelles. (shrink)

Cells fine‐tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV‐induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair‐defective diseases may involve repair‐transcription coupling: three (...) candidate genes have been suggested.However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription.Repair of other damage departs further from the paradigm, even in some UV‐mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV‐induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted. (shrink)

Signaling by the Epidermal Growth Factor Receptor (EGFR) and related ErbB family receptor tyrosine kinases can be deregulated in human malignancies as the result of mutations in the genes that encode these receptors. The recent identification of EGFR mutations that correlate with sensitivity and resistance to EGFR tyrosine kinase inhibitors in lung and colon tumors has renewed interest in such activating mutations. Here we review current models for ligand stimulation of receptor dimerization and for activation of receptor signaling by (...) receptor dimerization. In the context of these models, we discuss ErbB receptor mutations that affect ligand binding and those that cause constitutive receptor phosphorylation and signaling as a result of constitutive receptor dimerization. We discuss mutations in the cytoplasmic regions that affect enzymatic activity, substrate specificity and coupling to effectors and downstream signaling pathways. Finally, we discuss how emergent mechanisms of ErbB receptor mutational activation could impact the search for clinically relevant ErbB receptor mutations. BioEssays 29:558–565, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Recently, Gao et al. and Chappie et al. elucidated the crystal structures of the polytetrameric stalk domain of the dynamin‐like virus resistance protein, MxA, and of the G‐domain dimer of the large, membrane‐deforming GTPase, dynamin, respectively. Combined, they provide a hypothetical oligomeric structure for the complete dynamin protein. Here, it is discussed how the oligomers are expected to form and how they participate in dynamin mediated vesicle fission during the process of endocytosis. The proposed oligomeric structure is compared with the (...) novel mechanochemical model of dynamin function recently proposed by Bashkirov et al. and Pucadyil and Schmid. In conclusion, the new model of the dynamin oligomer has the potential to explain how short self‐limiting fissogenic dynamin assemblies are formed and how concerted GTP hydrolysis is achieved. The oligomerisation of two other dynamin superfamily proteins, the guanylate binding proteins (GBPs) and the immunity‐related GTPases (IRGs), is addressed briefly. (shrink)

The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high variability of the (...) BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Neurotrophins are a small family of dimeric secretory proteins in vertebrate neurons with a broad spectrum of functions. They are generated as pro‐proteins with a functionality that is distinct from the proteolytically processed form. The cellular responses of neurotrophins are mediated by three different types of receptor proteins, the receptor tyrosine kinases of the Trk family, the neurotrophin receptor p75NTR, which is a member of the tumor necrosis factor receptor (TNFR) superfamily, and sortilin, previously characterized as neurotensin receptor. Recent studies (...) have revealed an intriguing pattern: neurotrophins can elicit opposing signals utilising their variable configuration and different receptor types. BioEssays 28: 583–594, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

It has long been believed that membrane proteins present in degradative compartments such as endolysosomes or vacuoles would be destined for destruction. Now however, it appears that mechanisms and machinery exist in simple eukaryotes such as yeast and more complex organisms such as mammals that can rescue potentially “doomed” membrane proteins by retrieving them from these “late” compartments and recycling them back to the Golgi complex. In yeast, a sorting nexin dimer containing Snx4p can recognize and retrieve the Atg27p membrane (...) protein while in mammals, the AP5 complex (with SPG11 and SPG15) directs the recycling of Golgi‐localized proteins along with the cation‐independent mannose 6‐phosphate receptor (CIMPR). Although the respective machinery is different, there is much commonality between yeast and mammals regarding the mechanisms of retrieval and the physiological importance of these late recycling pathways. (shrink)

The assembly of intermediate filaments is a fundamental property of the central rod domain of the individual subunit proteins. This rod domain, with its high propensity for α‐helix formation, is the common and identifying feature of this family of proteins. Assembly occurs in vitro in the absence of other proteins or exogenous sources of energy; in vivo, it appears as if other factors, as yet poorly understood, modulate the assembly of intermediate filaments. Parallel, in‐register dimers form via coiled‐coil interactions of (...) the rod domain. Tetramers may form from staggered arrays of parallel or antiparallel arrangements of dimers. Higher‐order polymerization, which occurs spontaneously if the ionic strength of a mixture of dimers and tetramers is raised, proceeds rapidly through poorly described intermediates to the final 10 nm filament. This process is dependent on and modulated by the non‐α‐helical end domains, as well as those amino acids present at the very beginning and end of the rod domain. The interactions governing tetramer formation are most probably the same ones that are responsible for the lateral and longitudinal associations within intermediate filaments. (shrink)

Together with microtubules and actin microfilaments, ∼11 nm wide intermediate filaments (IFs) constitute the integrated, dynamic filament network present in the cytoplasm of metazoan cells. This network is critically involved in division, motility and other cellular processes. While the structures of microtubules and microfilaments are known in atomic detail, IF architecture is presently much less understood. The elementary ‘building block’ of IFs is a highly elongated, rod‐like dimer based on an α‐helical coiled‐coil structure. Assembly of cytoplasmic IF proteins, such as (...) vimentin, begins with a lateral association of dimers into tetramers and gradually into the so‐called unit‐length filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately yielding mature IFs after a compaction step. For nuclear lamins, however, assembly starts with a head‐to‐tail association of dimers. Recently, X‐ray crystallographic data were obtained for several fragments of the vimentin dimer. Based on the dimer structure, molecular models of the tetramer and the entire filament are now a possibility. BioEssays 25:243–251, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Microtubules form a highly dynamic filament network in all eukaryotic cells. Individual microtubules grow by tubulin dimer subunit addition and frequently switch between phases of growth and shortening. These unique dynamics are powered by GTP hydrolysis and drive microtubule network remodeling, which is central to eukaryotic cell biology and morphogenesis. Yet, our knowledge of the molecular events at growing microtubule ends remains incomplete. Here, recent ultrastructural, biochemical and cell biological data are integrated to develop a realistic model of growing microtubule (...) ends comprised of structurally distinct but biochemically overlapping zones. Proteins that recognize microtubule lattice conformations associated with specific tubulin guanosine nucleotide states may independently control major structural transitions at growing microtubule ends. A model is proposed in which tubulin dimer addition and subsequent closure of the MT wall are optimized in cells to achieve rapid physiological microtubule growth. (shrink)

Broad‐complex, Tramtrack, and Bric‐à‐brac/poxvirus and zinc finger (BTB/POZ) is a conserved domain found in many eukaryotic proteins with diverse cellular functions. Recent studies revealed its importance in multiple developmental processes as well as in the onset and progression of oncological diseases. Most BTB domains can form multimers and selectively interact with non‐BTB proteins. Structural studies of BTB domains delineated the presence of different interfaces involved in various interactions mediated by BTBs and provided a basis for the specific inhibition of distinct (...) protein‐interaction interfaces. BTB domains originated early in eukaryotic evolution and progressively adapted their structural elements to perform distinct functions. In this review, we summarize and discuss the structural principles of protein‐protein interactions mediated by BTB domains based on the recently published structural data and advances in protein modeling. We propose an update to the structure‐based classification of BTB domain families and discuss their evolutionary interconnections. (shrink)

Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, have been (...) proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors. (shrink)

Three apparently unrelated developmental processes – mammalian myogenesis, the choice of neural fate and sex determination in Drosophila – are controlled by a common mechanism. Most of the genes governing these processes encode transcriptional factors that contain the helix‐loop‐helix (HLH) motif. This domain mediates the formation of homo‐ or heterodimers that specifically bind to DNA through a conserved basic region adjacent to the HLH motif. Dimers differ in their affinity for DNA and in their ability to activate transcription from HLH (...) binding‐site containing promoters. In addition, the activity of HLH proteins is inhibited by dimerization with another class of HLH proteins that lack a basic domain entirely or have an altered one. These structural properties provide a molecular mechanism to explain the synergistic and antagonistic functional relations among the HLH encoding genes that control several developmental pathways. (shrink)

Just as the faithful replication of DNA is an essential process for the cell, chromatin structures of active and inactive genes have to be copied accurately. Under certain circumstances, however, the activity pattern has to be changed in specific ways. Although analysis of specific aspects of these complex processes, by means of model systems, has led to their further elucidation, the mechanisms of chromatin replication in vivo are still controversial and far from being understood completely. Progress has been achieved in (...) understanding: 1. The initiation of chromatin replication, indicating that a nucleosome‐free origin is necessary for the initiation of replication; 2. The segregation of the parental nucleosomes, where convincing data support the model of random distribution of the parental nucleosomes to the daughter strands; and 3. The assembly of histones on the newly synthesized strands, where growing evidence is emerging for a two‐step mechanism of nucleosome assembly, starting with the deposition of H3/H4 tetramers onto the DNA, followed by H2A/H2B dimers. (shrink)

The proteins encoded by early region 1 A (E1A) of human adenoviruses (Ad) modulate the expression of both adenovirus genes and various host cell genes. With these transcription‐regulating properties the E1A proteins redirect the cell's metabolism, which enables them to induce oncogenic transformation in rodent cells. The E1A proteins modulate transcription by interacting both with gene‐specific and general cellular transcription factors. Various members of the AP‐1 and ATF/CREB families of transcription factors are targets for E1A‐dependent regulation, including cJun, the protein (...) product of the c‐jun proto‐oncogene. The E1A proteins modulate cJun‐dependent transcription both positively and negatively, and affect the activity as well as the expression levels of cJun. By increasing the phosphorylation status of cJun, E1A can stimulate transcription regulated by cJun/ATF2 heterodimers. In contrast, E1A inhibits the expression of various metalloproteases by interfering with the DNA‐binding capacity of cJun/cJun and cJun/cFos dimers, which might involve the association of E1A with the putative transcriptional coactivator p300. Since the ability of E1A to alter cJun‐dependent transcription correlates with its transforming capacity, interference with cJundependent transcription may be an essential step in E1A‐induced transformation. (shrink)

It has long been thought that transmembrane cell‐surface receptors, such as receptor tyrosine kinases and cytokine receptors, among others, are activated by ligand binding through ligand‐induced dimerization of the receptors. However, there is growing evidence that prior to ligand binding, various transmembrane receptors have a preformed, yet inactive, dimeric structure on the cell surface. Various studies also demonstrate that during transmembrane signaling, ligand binding to the extracellular domain of receptor dimers induces a rotation of transmembrane domains, followed by rearrangement (...) and/or activation of intracellular domains. The paper here describes transmembrane cell‐surface receptors that are known or proposed to exist in dimeric form prior to ligand binding, and discusses how these preformed dimers are activated by ligand binding. (shrink)