Abstract

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.