A new split β‐lactamase assay promises experimental testing of the interplay of protein stability and function. Proteins are sufficiently stable to act effectively within cells. However, mutations generally destabilize structure, with effects on free energy that are comparable to the free energy of folding. Assays of protein functionality and stability in vivo enable a quick study of factors that influence these properties in response to targeted mutations. These assays can help molecular engineering but can also be used to (...) target important questions, including why most proteins are marginally stable, how mutations alter structural makeup, and how thermodynamics, function, and environment shape molecular change. Processes of self‐organization and natural selection are determinants of stability and function. Non‐equilibrium thermodynamics provides crucial concepts, e.g., cells as emergent energy‐dissipating entities that do work and build their own parts, and a framework to study the sculpting role of evolution at different scales. (shrink)

In this paper we propose a theoretical model of protein folding and protein evolution in which a polypeptide (sequence/structure) is assumed to behave as a Maxwell Demon or Information Gathering and Using System (IGUS) that performs measurements aiming at the construction of the native structure. Our model proposes that a physical meaning to Shannon information (H) and Chaitin's algorithmic information (K) parameters can be both defined and referred from the IGUS standpoint. Our hypothesis accounts for the interdependence (...) of protein folding and protein evolution through mutual influencing relationships mediated by the IGUS. In brief, IGUS activity in protein folding determines long term tendencies that emerge at the evolutionary time-scale.Thus, protein evolution is a consequence of measurements executed by proteins at the cellular level, where the IGUS imposes a tendency to attain a highly unique stable native form that promotes the updating of the information content. The folding kinetics observed is, thus, the outcome of an evolutionary process where the polypeptide-IGUS drives the evolution of its linear sequence. Finally, we describe protein evolution as an entropic process that tends to increase the content of mutual algorithmic information between the sequence and the structure. This model enables one: 1. To comprehend that full determination of the three-dimensional structure by the linear sequence is a tendency where satisfaction is only possible at thermodynamic equilibrium .2. To account for the observed randomness of the amino acid sequences. 3. To predict an alternation of periods of selection and neutral diffusion during protein evolutionary time. (shrink)

The gelsolin gene family encodes a number of higher eukaryotic actin-binding proteins that are thought to function in the cytoplasm by severing, capping, nucleating or bundling actin filaments. Recent evidence, however, suggests that several members of the gelsolin family may have adopted unexpected nuclear functions including a role in regulating transcription. In particular, flightless I, supervillin and gelsolin itself have roles as coactivators for nuclear receptors, despite the fact that their divergence appears to predate the evolutionary appearance of nuclear receptors. (...) Flightless I has been shown to bind both actin and the actin-related BAF53a protein, which are subunits of SWI/SNF-like chromatin remodelling complexes. The primary sequences of some actin-related proteins such as BAF53a exhibit conservation of residues that, in actin itself, are known to interact with gelsolin-related proteins. In summary, there is a growing body of evidence supporting a biological role in the nucleus for actin, Arps and actin-binding proteins and, in particular, the gelsolin family of actin-binding proteins. (c) 2005 Wiley Periodicals, Inc. (shrink)

Several DNA-damage detection and repair mechanisms have evolved to repair double-strand breaks induced by mutagens. Later in evolutionary history, DNA single- and double-strand cuts made possible immune diversity by V(D)J recombination and recombination at meiosis. Such cuts are induced endogenously and are highly regulated and controlled. In meiosis, DNA cuts are essential for the initiation of homologous recombination, and for the formation of joint molecule and crossovers. Many proteins that function during somatic DNA-damage detection and repair are also active during (...) homologous recombination. However, their meiotic functions may be altered from their somatic roles through localization, posttranslational modifications and/or interactions with meiosis-specific proteins. Presumably, somatic repair functions and meiotic recombination diverged during evolution, resulting in adaptations specific to sexual reproduction. BioEssays 27:795–808, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

It is presumed that the evolution of morphological diversity in animals and plants is driven by changes in the developmental processes that govern morphology, hence basically by changes in the function and/or expression of a defined set of genes that control these processes. A large body of evidence has suggested that changes in developmental gene regulation are the predominant mechanisms that sustain morphological evolution, being much more important than the evolution of the primary sequences and functions of (...) proteins. Recent reports1, 2 challenge this idea by highlighting functional evolution of Hox proteins during the evolutionary history of arthropods. BioEssays 24:775–779, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Recently published work showed that members of the PAQR protein family are activated by cell membrane rigidity and contribute to our ability to eat a wide variety of diets. Cell membranes are primarily composed of phospholipids containing dietarily obtained fatty acids, which poses a challenge to membrane properties because diets can vary greatly in their fatty acid composition and could impart opposite properties to the cellular membranes. In particular, saturated fatty acids (SFAs) can pack tightly and form rigid membranes (...) (like butter at room temperature) while unsaturated fatty acids (UFAs) form more fluid membranes (like vegetable oils). Proteins of the PAQR protein family, characterized by the presence of seven transmembrane domains and a cytosolic N‐terminus, contribute to membrane homeostasis in bacteria, yeasts, and animals. These proteins respond to membrane rigidity by stimulating fatty acid desaturation and incorporation of UFAs into phospholipids and explain the ability of animals to thrive on diets with widely varied fat composition. Also see the video abstract here: https://youtu.be/6ckcvaDdbQg. (shrink)

Vertebrate haemoglobin (Hb), the oxygen‐carrying protein of the blood, consists of two α‐ and two β‐subunits, each containing one haem, and shows cooperative oxygen binding known as the haem–haem interaction. The amino‐acid sequences of Hbs found in different species have diverged considerably and the homology in the most distantly related ones is only 40%. How can such varied amino‐acid sequences give rise to similar three‐dimensional structures and functional properties? To what extent do amino‐acid replacements affect the structure of haemoglobin? (...) Which mutations are responsible for the functional differences between haemoglobins from different species? Expression of α‐ and β‐globins in Escherichia coli has enabled us to introduce any mutations in the haemoglobin molecule at will. By X‐ray crystallographic and functional studies of the engineered mutants, we are trying to answer these questions. (shrink)

A crucially important part of the biosphere – the virosphere – is too often overlooked. Inclusion of the virosphere into the global picture of protein structure space reveals that 63 protein domain superfamilies in viruses do not have any structural and evolutionary relatives in modern cellular organisms. More than half of these have functions which are not virus‐specific and thus might be a source of new folds and functions for cellular life. The number of viruses on the planet (...) exceeds that of cells by an order of magnitude and viruses evolve up to six orders of magnitude faster. As a result, cellular species are subject to a constitutive ‘flow‐through’ of new viral genetic material. Due to this and the relaxed evolutionary constraints in viruses, the transfer of domains between host‐to‐virus could be a mechanism for accelerated protein evolution. The virosphere could be an engine for the genesis of protein structures, and may even have been so before the last universal common ancestor of cellular life. (shrink)

Protein structure is dynamic: the intrinsic flexibility of polypeptides facilitates a range of conformational fluctuations, and individual protein chains can assemble into complexes. Proteins are also dynamic in evolution: significant variations in secondary, tertiary and quaternary structure can be observed among divergent members of a protein family. Recent work has highlighted intriguing similarities between these structural and evolutionary dynamics occurring at various levels. Here we review evidence showing how evolutionary changes in protein sequence and structure (...) are often closely related to local protein flexibility and disorder, large‐scale motions and quaternary structure assembly. We suggest that these correspondences can be largely explained by neutral evolution, while deviations between structural and evolutionary dynamics can provide valuable functional insights. Finally, we address future prospects for the field and practical applications that arise from a deeper understanding of the intimate relationship between protein structure, dynamics, function and evolution. (shrink)

Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels in their chemical and catalytic underpinnings. Here, focussing on modifications that involve the addition of new elements to amino‐acid sidechains, I describe historical milestones and fundamental concepts that support the current understanding of PTMs. The historical survey covers selected key research programmes, including the study of protein phosphorylation (...) as a regulatory switch, protein ubiquitylation as a degradation signal and histone modifications as a functional code. The contribution of crucial techniques for studying PTMs is also discussed. The central part of the essay explores shared chemical principles and catalytic strategies observed across diverse PTM systems, together with mechanisms of substrate selection, the reversibility of PTMs by erasers and the recognition of PTMs by reader domains. Similarities in the basic chemical mechanism are highlighted and their implications are discussed. The final part is dedicated to the evolutionary trajectories of PTM systems, beginning with their possible emergence in the context of rivalry in the prokaryotic world. Together, the essay provides a unified perspective on the diverse world of major protein modifications. (shrink)

In the eukaryotic cell, DNA compaction is achieved through its interaction with histones, constituting a nucleoprotein complex called chromatin. During metazoan evolution, the different structural and functional constraints imposed on the somatic and germinal cell lines led to a unique process of specialization of the sperm nuclear basic proteins (SNBPs) associated with chromatin in male germ cells. SNBPs encompass a heterogeneous group of proteins which, since their discovery in the nineteenth century, have been studied extensively in different organisms. However, (...) the origin and controversial mechanisms driving the evolution of this group of proteins has only recently started to be understood. Here, we analyze in detail the histone hypothesis for the vertical parallel evolution of SNBPs, involving a “vertical” transition from a histone to a protamine‐like and finally protamine types (H → PL → P), the last one of which is present in the sperm of organisms at the uppermost tips of the phylogenetic tree. In particular, the common ancestry shared by the protamine‐like (PL)‐ and protamine (P)‐types with histone H1 is discussed within the context of the diverse structural and functional constraints acting upon these proteins during bilaterian evolution. (shrink)

The actin crosslinking proteins exhibit marked diversity in size and shape and crosslink actin filaments in different ways. Amino acid sequence analysis of many of these proteins has provided clues to the origin of their diversity. Spectrin, α‐actinin, ABP‐120, ABP‐280, fimbrin, and dystrophin share a homologous sequence segment that is implicated as the common actin binding domain. The remainder of each protein consists of repetitive and non‐repetitive sequence segments that have been shuffled and multiplied in evolution to produce (...) a variety of proteins that are related in function and in composition, but that differ significantly in structure. (shrink)

At first glance the three eukaryotic protein translocation machineries – the ER‐associated degradation (ERAD) transport apparatus of the endoplasmic reticulum, the peroxisomal importomer and SELMA, the pre‐protein translocator of complex plastids – appear quite different. However, mechanistic comparisons and phylogenetic analyses presented here suggest that all three translocation machineries share a common ancestral origin, which highlights the recycling of pre‐existing components as an effective evolutionary driving force.Editor's suggested further reading in BioEssays ERAD ubiquitin ligases Abstract.

While Darwin pictured organismal evolution as “descent with modification” more than 150 years ago, a detailed reconstruction of the basic evolutionary transitions at the molecular level is only emerging now. In particular, the evolution of today's protein structures and their concurrent functions has remained largely mysterious, as the destruction of these structures by mutation seems far easier than their construction. While the accumulation of genomic and structural data has indicated that proteins are related via common ancestors, naturally (...) occurring protein structures are often considered to be evolutionarily robust, thus leaving open the question of how protein structures can be remodelled while selective pressure forces them to function. New information on the proteome, however, increasingly explains the nature of local and global conformational diversity in protein evolution, which allows the acquisition of novel functions via molecular transition forms containing ancestral and novel structures in dynamic equilibrium. Such structural plasticity may permit the evolution of new protein folds and help account for both the origins of new biological functions and the nature of molecular defects. BioEssays 29:1095–1104, 2007. © 2007 Wiley Periodicals, Inc. (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)

Despite their seemingly endless diversity, proteins adopt a limited number of structural forms. It has been estimated that 80% of proteins will be found to adopt one of only about 400 folds, most of which are already known. These folds are largely formed by a limited ‘vocabulary’ of recurring supersecondary structure elements, often by repetition of the same element and, increasingly, elements similar in both structure and sequence are discovered. This suggests that modern proteins evolved by fusion and recombination from (...) a more ancient peptide world and that many of the core folds observed today may contain homologous building blocks. The peptides forming these building blocks would not in themselves have had the ability to fold, but would have emerged as cofactors supporting RNA‐based replication and catalysis (the ‘RNA world’). Their association into larger structures and eventual fusion into polypeptide chains would have allowed them to become independent of their RNA scaffold, leading to the evolution of a novel type of macromolecule: the folded protein. BioEssays 25:837–846, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Spiders spin multiple types of silks that are renowned for their superb mechanical properties. Flagelliform silk, used in the capture spiral of an orb‐web, is one of the few silks characterized by both cDNA and genomic DNA data. This fibroin is composed of repeating ensembles of three types of amino acid sequence motifs. The predominant subrepeat, GPGGX, likely forms a β‐turn, and tandem arrays of these turns are thought to create β‐spirals. These spring‐like helices may be critical for the exceptional (...) ability of capture silk to stretch and recoil. Each ensemble of motifs was found to correspond to a different exon within the flagelliform gene. The pattern of sequence similarity among exons indicates intragenic concerted evolution. Surprisingly, the introns between the iterated exons are also homogenized with each other. This unusual molecular architecture in the flagelliform silk gene has implications for the evolution and maintenance of spider silk proteins. BioEssays 23:750–756, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Fold‐switching proteins, which remodel their secondary and tertiary structures in response to cellular stimuli, suggest a new view of protein fold space. For decades, experimental evidence has indicated that protein fold space is discrete: dissimilar folds are encoded by dissimilar amino acid sequences. Challenging this assumption, fold‐switching proteins interconnect discrete groups of dissimilar protein folds, making protein fold space fluid. Three recent observations support the concept of fluid fold space: (1) some amino acid sequences interconvert between (...) folds with distinct secondary structures, (2) some naturally occurring sequences have switched folds by stepwise mutation, and (3) fold switching is evolutionarily selected and likely confers advantage. These observations indicate that minor amino acid sequence modifications can transform protein structure and function. Consequently, proteomic structural and functional diversity may be expanded by alternative splicing, small nucleotide polymorphisms, post‐translational modifications, and modified translation rates. (shrink)

Different families of transport proteins catalyze transmembrane solute translocation, employing different mechanisms and energy sources. Several of these functionally dissimilar proteins nevertheless exhibit similar strutural units, consisting of six tightly packed α‐helices which may comprise all or part of a transmembrane channel. It is now recognized that some of these families arose independently of each other by convergence, while others arose from common precursors by divergence. The former families apparently arose at different times in evolutionary history, in different groups of (...) organisms, employing different routes. (shrink)

The alcohol‐soluble (prolamin) storage proteins of barley, wheat and rye vary in their structures, but all have two features in common: the presence of distinct structural domains differing in amino acid compositions, and of repeats within one of these domains. Detailed comparisons of amino acid sequences show that all appear to have evolved from a single ancestral gene consisting of three short related regions (called A, B and C). Regions related to A, B and C are also present in the (...) minor prolamins of maize and in three other groups of seed proteins: inhibitors of α‐amylase and /or trypsin from cereals. 2S storage globulins from several dicotyledonous species and a 2S albumin from sunflower. It is suggested that these proteins together constitute a protein superfamily with limited sequence homology. (shrink)

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in (...) every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. (shrink)

In contrast to vertical gene transfer from parent to offspring, horizontal (or lateral) gene transfer moves genetic information between different species. Bacteria and archaea often adapt through horizontal gene transfer. Recent analyses indicate that eukaryotic genomes, too, have acquired numerous genes via horizontal transfer from prokaryotes and other lineages. Based on this we raise the hypothesis that horizontally acquired genes may have contributed more to adaptive evolution of eukaryotes than previously assumed. Current candidate sets of horizontally acquired eukaryotic genes (...) may just be the tip of an iceberg. We have recently shown that adaptation of the thermoacidophilic red algaGaldieria sulphurariato its hot, acid, toxic‐metal laden, volcanic environment was facilitated by the acquisition of numerous genes from extremophile bacteria and archaea. Other recently published examples of horizontal acquisitions involved in adaptation include ice‐binding proteins in marine algae, enzymes for carotenoid biosynthesis in aphids, and genes involved in fungal metabolism.Editor's suggested further reading in BioEssaysJumping the fine LINE between species: Horizontal transfer of transposable elements in animals catalyses genome evolution Abstract. (shrink)

In a recent paper, Merabet and Hudry discuss models explaining the functional evolution of fushi tarazu (ftz) from an ancestral homeotic to a pair‐rule segmentation gene in Drosophila. As most of the experimental work underlying these models comes from our research, we wish to reply to Merabet and Hudry providing an explanation of the experimental approaches and logical framework underlying them. We review experimental data that support our hypotheses and discuss misconceptions in the literature. We emphasize that the change (...) in ftz function required changes in both expression pattern and protein function and review the evidence that these functional changes involved a switch in cofactor‐interaction motifs during arthropod radiations. While agreeing with Merabet and Hudry that protein context likely contributes to Ftz function, we argue that until supporting evidence for alternative mechanisms is obtained, the role of cofactor‐interaction motifs in driving a functional switch remains compelling. (shrink)

Recent experimental data from proteomics and genomics are interpreted here in ways that challenge the predominant viewpoint in biology according to which the four evolutionary processes, including mutation, recombination, natural selection and genetic drift, are sufficient to explain the origination of species. The predominant viewpoint appears incompatible with the finding that the sequenced genome of each species contains hundreds, or even thousands, of unique genes - the genes that are not shared with any other species. These unique genes and proteins, (...) singletons, define the very character of every species. Moreover, the distribution of protein families from the sequenced genomes indicates that the complexity of genomes grows in a manner different from that of self-organizing networks: the dominance of singletons leads to the conclusion that in living organisms a most unlikely phenomenon can be the most common one. In order to provide proper rationale for these conclusions related to the singletons, the paper first treats the frequency of functional proteins among random sequences, followed by a discussion on the protein structure space, and it ends by questioning the idea that protein domains represent conserved units of evolution. (shrink)

The cellular processes of transport, division and, possibly, early development all involve microtubule‐based motors. Recent work shows that, unexpectedly, many of these cellular functions are carried out by different types of kinesin and kinesin‐related motor proteins. The kinesin proteins are a large and rapidly growing family of microtubule‐motor proteins that share a 340‐amino‐acid motor domain. Phylogenetic analysis of the conserved motor domains groups the kinesin proteins into a number of subfamilies, the members of which exhibit a common molecular organization and (...) related functions. The kinesin proteins that belong to different subfamilies differ in their rates and polarity of movement along microtubules, and probably in the particles/organelles that they transport. The kinesins arose early in eukaryotic evolution and gene duplication has allowed functional specialization to occur, resulting in a surprisingly large number of different classes of these proteins adapted for intracellular transport of vesicles and organelles, and for assembly and force generation in the meiotic and mitotic spindles. (shrink)

The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post‐translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications utilized to regulate (...) Hh signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis (...) of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

This essay moves along broad lines from molecular biology to evolutionary biology and ecology to theology. Its objectives are to: 1) present some recent scientific findings in the emerging field of epigenetics that indicate that it is “the genome in context,” not genes per se, that are important in biological development and evolution; 2) show that this weakens the gene-centric neo-Darwinist explanation of evolution which, in fact, shares a certain preformationist orientation with intelligent design theory; 3) argue that (...) the evidence against a gene-centric view in no way negates Darwin’s central idea of “descent with modification”; 4) argue that an embrace of the evolutionary story, with all of its contingency and apparent lack of directionality, is not only consistent with Christianity, but actually resonates with the notion of the self-emptying love of God in Jesus Christ; and finally 5) suggest that we are called through an ecological imperative to embrace our evolutionary story, to listen to our “genetic coding,” and to reclaim our grounding as a species in the natural world. Corrigendum (published in later issue of journal): There was an error in the paragraph describing the mode of action of the small temporally-expressed RNAs (stRNAs) lin-4 and let-7 from Caenorhabditis elegans. Instead of reading "These two stRNAs act by binding to the tails of their target messenger RNAs (mRNAs); this results in destruction of the target and an overall drop in the level of production of protein from agouti mRNA" [note that agouti mRNA is not a target of these stRNAs], the sentence should have read, "These two stRNAs act by binding to the tails of target messenger RNAs (mRNAs); this leads to inhibition of translation of the mRNAs into protein and a consequent drop in the levels of the corresponding target protein.". (shrink)

Selective protein degradation maintains cellular homeostasis, but this process is disrupted in many diseases. Targeted protein degradation (TPD) approaches, built upon existing cellular mechanisms, are promising methods for therapeutically regulating protein levels. Here, we review the diverse palette of tools that are now available for doing so throughout the gene expression pathway and in specific cellular compartments. These include methods for directly removing targeted proteins via the ubiquitin proteasome system with proteolysis targeting chimeras (PROTACs) or dephosphorylation targeting (...) chimeras (DEPTACs). Similar effects can also be achieved through the lysosomal system with autophagy‐targeting chimeras (AUTACs), autophagosome tethering compounds (ATTECs), and lysosome targeting chimeras (LYTACs). Other methods act upstream to degrade RNAs (ribonuclease targeting chimeras; RIBOTACs) or transcription factors (transcription factor targeting chimeras; TRAFTACs), offering control throughout the gene expression process. We highlight the evolution and function of these methods and discuss their clinical implications in diverse disease contexts. (shrink)

To explore whether the generation of new protein folds could be linked to metallic cofactor recruitment, we identified the oldest examples of folds for manganese, iron, zinc, and copper proteins by analyzing their fold‐domain mapping patterns. We discovered that the generation of these folds was tightly coupled to corresponding metals. We found that the emerging order for these folds, i.e., manganese and iron protein folds appeared earlier than zinc and copper counterparts, coincides with the putative bioavailability of the (...) corresponding metals in the ancient anoxic ocean. Therefore, we conclude that metallic cofactors, like organic cofactors, play an evolutionary role in the formation of new protein folds. This link could be explained by the emergence of protein structures with novel folds that could fulfill the new protein functions introduced by the metallic cofactors. These findings not only have important implications for understanding the evolutionary mechanisms of protein architectures, but also provide a further interpretation for the evolutionary story of superoxide dismutases. (shrink)

A philosophically comprehended account is given of the genesis and evolution of the concept of protein. Characteristic of this development were not shifts in theory in response to new experimental data, but shifts in the range of questions that the available experimental resources were fit to cope with effectively. Apart from explanatory success with regard to its own range of questions, various other selecting factors acted on a conceptual variant, some stemming from a competing set of research questions, (...) others from an altogether different field of inquiry, and still others from the external environment. These results are best explained on, hence support, an evolutionary model of the progress of experimental investigation, whose outlines are briefly discussed. (shrink)

There are currently three major theories on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and the error-minimization theory. The first two assume that the genetic code originated respectively from chemical affinities and from metabolic relationships between codons and amino acids. The error-minimization theory maintains that in primitive systems the apparatus of protein synthesis was extremely prone to errors, and postulates that the genetic code evolved in order to minimize the deleterious effects (...) of the translation errors. This article describes a fourth theory which starts from the hypothesis that the ancestral genetic code was ambiguous and proposes that its evolution took place with a mechanism that systematically reduced its ambiguity and eventually removed it altogether. This proposal is distinct from the stereochemical and the coevolution theories because they do not contemplate any ambiguity in the genetic code, and it is distinct from the error-minimization theory because ambiguity-reduction is fundamentally different from error-minimization. The concept of ambiguity-reduction has been repeatedly mentioned in the scientific literature, but so far it has remained only an abstract possibility because no model has been proposed for its mechanism. Such a model is described in the present article and may be the first step in a new approach to the study of the evolution of the genetic code. (shrink)

Recent sequencing of the metazoan Oikopleura dioica genome has provided important insights, which challenges the current understanding of eukaryotic genome evolution. Many genomic features of O. dioica show deviation from the commonly observed trends in other eukaryotic genomes. For instance, O. dioica has a rapidly evolving, highly compact genome with a divergent intron‐exon organization. Additionally, O. dioica lacks the minor spliceosome and key DNA repair pathway genes. Even with a compact genome, O. dioica contains tandem repeats, comparable to other (...) eukaryotes, and shows lineage‐specific expansion of certain protein domains. Here, we review its genomic features in the context of current knowledge, discuss implications for contemporary biology and identify areas for further research. Analysis of the O. dioica genome suggests that non‐adaptive forces such as elevated mutation rates might influence the evolution of genome architecture. The knowledge of unique genomic features and splicing mechanisms in O. dioica may be exploited for synthetic biology applications, such as generation of orthogonal splicing systems. (shrink)

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of (...) protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress. (shrink)

Some nuclear‐encoded proteins are imported into higher plant plastids via the endomembrane (EM) system. Compared with multi‐protein Toc and Tic translocons required for most plastid protein import, the relatively uncomplicated nature of EM trafficking led to suggestions that it was the original transport mechanism for nuclear‐encoded endosymbiont proteins, and critical for the early stages of plastid evolution. Its apparent simplicity disappears, however, when EM transport is considered in light of selective constraints likely encountered during the conversion of (...) stable endosymbionts into fully integrated organelles. From this perspective it is more parsimonious to presume the early evolution of post‐translational protein import via simpler, ancestral forms of modern Toc and Tic plastid translocons, with EM trafficking arising later to accommodate glycosylation and/or protein targeting to multiple cellular locations. This hypothesis is supported by both empirical and comparative data, and is consistent with the relative paucity of EM‐based transport to modern primary plastids. (shrink)

Comparative genomics has proven a fruitful approach to acquire many functional and evolutionary insights into core cellular processes. Here it is argued that in order to perform accurate and interesting comparative genomics, one first and foremost has to be able to recognize, postulate, and revise different evolutionary scenarios. After all, these studies lack a simple protocol, due to different proteins having different evolutionary dynamics and demanding different approaches. The authors here discuss this challenge from a practical (what are the observations?) (...) and conceptual (how do these indicate a specific evolutionary scenario?) viewpoint, with the aim to guide investigators who want to analyze the evolution of their protein(s) of interest. By sharing how the authors draft, test, and update such a scenario and how it directs their investigations, the authors hope to illuminate how to execute molecular evolution studies and how to interpret them. Also see the video abstract here https://youtu.be/VCt3l2pbdbQ. (shrink)

There are two intriguing paradoxes in molecular biology-the inconsistent relationship between organismal complexity and (1) cellular DNA content and (2) the number of protein-coding genes-referred to as the C-value and G-value paradoxes, respectively. The C-value paradox may be largely explained by varying ploidy. The G-value paradox is more problematic, as the extent of protein coding sequence remains relatively static over a wide range of developmental complexity. We show by analysis of sequenced genomes that the relative amount of non- (...) class='Hi'>protein-coding sequence increases consistently with complexity. We also show that the distribution of introns in complex organisms is non-random. Genes composed of large amounts of intronic sequence are significantly overrepresented amongst genes that are highly expressed in the nervous system, and amongst genes downregulated in embryonic stem cells and cancers. We suggest that the informational paradox in complex organisms may be explained by the expansion of cis-acting regulatory elements and genes specifying trans-acting non-protein-coding RNAs. (shrink)

Minichromosome maintenance (Mcm) proteins are well‐known for their functions in DNA replication. However, their roles in chromosome segregation are yet to be reviewed in detail. Following the discovery in 1984, a group of Mcm proteins, known as the ARS‐nonspecific group consisting of Mcm13, Mcm16‐19, and Mcm21‐22, were characterized as bonafide kinetochore proteins and were shown to play significant roles in the kinetochore assembly and high‐fidelity chromosome segregation. This review focuses on the structure, function, and evolution of this group of (...) Mcm proteins. Our in silico analysis of the physical interactors of these proteins reveals that they share non‐overlapping functions despite being copurified in biochemically stable complexes. We have discussed the contrasting results reported in the literature and experimental strategies to address them. Taken together, this review focuses on the structure‐function of the ARS‐nonspecific Mcm proteins and their evolutionary flexibility to maintain genome stability in various organisms. (shrink)

Here I discuss findings that suggest a universal mechanism for proteins (and RNA) to recognize and interact with various binding partners by selectively binding to different conformations that pre‐exist in the free protein's conformational ensemble. The tandem RNA recognition motif domains of splicing factor U2AF65 fluctuate in solution between a predominately closed conformation in which the RNA binding site of one of the domains is blocked, and a lowly populated open conformation in which both RNA binding pockets are accessible. (...) RNA binding to U2AF65 may thus occur through the weakly populated open conformation, and the binding interaction stabilizes the open conformation. The conformational diversity observed in U2AF65 might also facilitate binding to diverse RNA sequences as found in the polypyrimidine tracts that help define 3′ splice sites. Similar binding pathways in other systems have important consequences in biological regulation, molecular evolution, and information storage. (shrink)

Retrotransposon-derived elements (RDEs) can disrupt gene expression, but are nevertheless widespread in metazoan genomes. This review presents a hypothesis that repressive RNA-binding proteins (RBPs) facilitate the large-scale accumulation of RDEs. Many RBPs bind RDEs in pre-mRNAs to repress the effects of RDEs on RNA processing, or the formation of inverted repeat RNA structures. RDE-binding RBPs often assemble on extended, multivalent binding sites across the RDE, which ensures repression of cryptic splice or polyA sites. RBPs thereby minimize the effects of RDEs (...) on gene expression, which likely reduces the negative selection against RDEs. While mutations that change splice sites in RDEs act as an off-on switch in exon formation, mutations that decrease the multivalency of RBP binding sites resemble a rheostat that enables a more gradual evolution of new RDE-derived exons. RBPs might also repress aberrant processing of active retrotransposons, thus increasing the chance that full-length copies are made. Taken together, in this review, it is proposed that RBPs facilitate the widespread accumulation of intronic RDEs by repressing RNA processing while chaperoning their potential to gradually evolve into new exons. (shrink)

Secreted Frizzled‐related proteins (SFRPs) are modulators of the intermeshing pathways in which signals are transduced by Wnt ligands through Frizzled (Fz) membrane receptors. The Wnt networks influence biological processes ranging from developmental cell fate, cell polarity and adhesion to tumorigenesis and apoptosis. In the five or six years since their discovery, the SFRPs have emerged as dynamically expressed proteins able to bind both Wnts and Fz, with distinctive structural properties in which cysteine‐rich domains from Fz‐ and from netrin‐like proteins are (...) juxtaposed. The abundant expression of SFRP genes in the early embryo, altered expression patterns in disease states, and potential significance in the evolution of the vertebrate body plan, make these intriguing molecules relevant to investigations in diverse fields of biology and biomedical sciences. BioEssays 24:811–820, 2002. © 2002 Wiley Periodicals, Inc. (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)

Graphical AbstractWhereas clathrin-mediated endocytosis (CME) exists in all eukaryotic cells, we first detect classical dynamin in Ichthyosporid, a single-cell, metazoan precursor. Based on a key functional residue in its pleckstrin homology domain, we speculate that the evolution of metazoan dynamin coincided with the specialized need for regulated CME during neurotransmission.

Horizontal gene transfer advances bacterial evolution. To benefit from horizontally acquired genes, enteric bacteria must overcome silencing caused when the widespread heat‐stable nucleoid structuring (H‐NS) protein binds to AT‐rich horizontally acquired genes. This ability had previously been ascribed to both anti‐silencing proteins outcompeting H‐NS for binding to AT‐rich DNA and RNA polymerase initiating transcription from alternative promoters. However, we now know that pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli break down H‐NS when this silencer is not (...) bound to DNA. Curiously, both species use the same protease – Lon – to destroy H‐NS in distinct environments. Anti‐silencing proteins promote the expression of horizontally acquired genes without binding to them by displacing H‐NS from AT‐rich DNA, thus leaving H‐NS susceptible to proteolysis and decreasing H‐NS amounts overall. Conserved amino acid sequences in the Lon protease and H‐NS cleavage site suggest that diverse bacteria degrade H‐NS to exploit horizontally acquired genes. (shrink)