Eukaryotic Protein Domains as Functional Units of Cellular Evolution

Abstract

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.

Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3)

“…Second, both RIN3 and CD2AP were among 21 proteins pulled down from kidney cells by the SH3-5/6 domains of the large adaptor protein TUBA (51). TUBA contains six SH3 domains and has guanine nucleotide exchange factor activity toward CDC42.…”

Modular evolution of phosphorylation-based signalling systems

“…In the case of the pTyr-binding SH2 domains, all 121 human family members are predicted to adopt a general structural fold consisting of a large seven-strand b-sheet flanked by two a-helices, and indeed there are solved structures for more than 60 SH2 domain family members [68,69]. Humans and yeast share only one related protein that possesses a sequence corresponding to an SH2 domain (Supt6H/ Spt6), and this is the only evident SH2-containing protein in yeast [53]. Structural analysis has shown that yeast Spt6 actually has two rigidly linked tandem SH2 domains, of which only the N-terminal domain (SH2N) was identified by sequence [70,71].…”

“…We have proposed that domains such as 14-3-3 that are never normally joined to other modules are maintained in this isolated state owing to their central role in numerous aspects of cellular regulation and organization, which might be corrupted by incorporation into a larger polypeptide [53]. An alternative possibility is that the joining of a 14-3-3 domain to another sequence might interfere with its structure and function on biophysical grounds.…”

“…The next step in the evolution of pTyr signalling appears to have been the selection of pTyrbinding SH2 domains. The slime mould Dictyostelium discoideum has a simple repertoire of 13 SH2 domains that are known or predicted to bind pTyr, among which are proteins resembling the metazoan STAT (signal transducer and activator of transcription) transcription factors and the Cbl E3 protein-ubiquitin ligase [53]. STATs dimerize through intermolecular pTyr-SH2 interactions, and translocate to the nucleus where they bind DNA and regulate the expression of specific genes.…”

The Plexus Model for the Inference of Ancestral Multidomain Proteins

“…The sequencing of higher eukaryote genomes revealed that many protein coding genes bear hallmarks of hybridization and recombination events [2]. Many such evolutionary cassettes fold into sizable, distinct units that can be easily recognized in the three-dimensional structures [30]. Other recognizable and frequent elements are short motifs.…”