Eukaryotic Protein Domains as Functional Units of Cellular Evolution

Clustering proteins into groups on the basis of their domain compositions provides insight into protein evolution. Domains for Change Protein domains endow proteins with specific activities and the ability to interact with specific partners. Most protein domains occur in many proteins and most proteins have multiple domains, but the combinations of domains are far fewer than would be predicted, suggesting that there is evolutionary pressure that preserves certain domain combinations. Jin et al. use a proteome-wide clustering method to identify eukaryotic protein domain combinations that correlate with evolutionary change. Their analysis suggests that reciprocal interactions between a protein and its microenvironment constrain the repertoire of domains that control specific cellular functions. They analyzed the proteins in seven eukaryotic species and organized the domains into 1245 “domain clubs,” with the majority of clubs containing proteins with multiple distinct domains and proteins with rich interrelationships among members of different clubs. They grouped proteins on the basis of their domain clubs into functional trees and were able to place domains of unknown function into functional groups, as well as make predictions about the role domain evolution contributes to the evolution of protein function within a molecular environment, as well as to the evolution of molecular environments. Modular protein domains are functional units that can be modified through the acquisition of new intrinsic activities or by the formation of novel domain combinations, thereby contributing to the evolution of proteins with new biological properties. Here, we assign proteins to groups with related domain compositions and functional properties, termed “domain clubs,” which we use to compare multiple eukaryotic proteomes. This analysis shows that different domain types can take distinct evolutionary trajectories, which correlate with the conservation, gain, expansion, or decay of particular biological processes. Evolutionary jumps are associated with a domain that coordinately acquires a new intrinsic function and enters new domain clubs, thereby providing the modified domain with access to a new cellular microenvironment. We also coordinately analyzed the covalent and noncovalent interactions of different domain types to assess the molecular compartment occupied by each domain. This reveals that specific subsets of domains demarcate particular cellular processes, such as growth factor signaling, chromatin remodeling, apoptotic and inflammatory responses, or vesicular trafficking. We suggest that domains, and the proteins in which they reside, are selected during evolution through reciprocal interactions with protein domains in their local microenvironment. Based on this scheme, we propose a mechanism by which Tudor domains may have evolved to support different modes of epigenetic regulation and suggest a role for the germline group of mammalian Tudor domains in Piwi-regulated RNA biology.