Evolution of domain–peptide interactions to coadapt specificity and affinity to functional diversity

Abstract

Evolution of complexity in eukaryotic proteomes has arisen, in part, through emergence of modular independently folded domains mediating protein interactions via binding to short linear peptides in proteins. Over 30 years, structural properties and sequence preferences of these peptides have been extensively characterized. Less successful, however, were efforts to establish relationships between physicochemical properties and functions of domainpeptide interactions. To our knowledge, we have devised the first strategy to exhaustively explore the binding specificity of protein domain-peptide interactions. We applied the strategy to SH3 domains to determine the properties of their binding peptides starting from various experimental data. The strategy identified the majority (∼70%) of experimentally determined SH3 binding sites. We discovered mutual relationships among binding specificity, binding affinity, and structural properties and evolution of linear peptides. Remarkably, we found that these properties are also related to functional diversity, defined by depth of proteins within hierarchies of gene ontologies. Our results revealed that linear peptides evolved to coadapt specificity and affinity to functional diversity of domain-peptide interactions. Thus, domain-peptide interactions follow human-constructed gene ontologies, which suggest that our understanding of biological process hierarchies reflect the way chemical and thermodynamic properties of linear peptides and their interaction networks, in general, have evolved.linear peptides | domain-peptide interactions | binding specificity | binding affinity | functional specificity M any proteins, particularly in eukaryotes, are composed of modular protein architectures consisting of multiple independently folding domains (1). Specific domains such as SH3 and PDZ domains were repeatedly used throughout evolution in increasingly complex organisms to mediate protein-protein interactions involved in signal transduction and protein targeting (2-5). These domains are associated with a number of human diseases and are targets of virus and other pathogen virulence proteins (6). Functions of these domains include binding to sequence-specific peptides both among themselves and on other proteins. Such interactions can create enormous plasticity in complex signaling and regulatory networks on immediate to evolutionary timescales (7), and are often used for regulating the activities of proteins and the spatiotemporal organization of protein interaction networks (8,9). However, at the cellular level, we still do not grasp why certain peptides in proteins bind to distinct domains with high specificity whereas others highly cross-react with a number of members of a family of domains, and also what is the relationship between specificity of binding and specificity of functions of domain-peptide interactions. Two extreme examples are peptides of the MAPKK protein Pbs2 (residues 92-106) (10) and the actin assembly protein Las17 (residues 306-336) (11), which both interact with ...

CellectSeq: In Silico Discovery of Antibodies Targeting Integral Membrane Proteins Combining In Situ Selections of Phage Displayed Synthetic Antibodies and Next-Generation Sequencing

“…This follows the premise that highly selective Abs are enriched with paratope motifs (i.e. linear information) that recognize the target antigen, whereas non-selective Abs lack such enrichment 45 ( Figure S6). Therefore, for each Ab clone in the positive pool (i.e.…”

TulsiPIN: an interologous protein interactome ofOcimum tenuiflorum

“…consisting of more than one domains 30 . Since different domains possess unique structures and biological functions, so they are believed to have been designed and evolved to interact with specific domains 56 . An average PPI hence is not determined by all the domains possessed by proteins participating in the interaction rather by a selected subset only 32,57 .…”

Protein context shapes the specificity of domain-peptide interactions in vivo

“…SH3s have expanded in numbers throughout the evolution of signaling networks, with 27 in yeast and nearly 300 members in humans (Vogel and Chothia, 2006;Teyra et al , 2017) . Not only have genes coding for SH3-containing proteins been duplicated, but SH3s themselves have been duplicated within proteins (Vogel, Teichmann and Pereira-Leal, 2005;Vogel and Chothia, 2006;Kelil, Levy and Michnick, 2016) . This led to the birth of a large number of proteins containing 2-3 SH3 copies, favoring the formation of higher order protein complexes through multivalent interactions and elaborate arrangements such as the ones leading to phase separation (Banjade and Rosen, 2014) .…”

“…This led to the birth of a large number of proteins containing 2-3 SH3 copies, favoring the formation of higher order protein complexes through multivalent interactions and elaborate arrangements such as the ones leading to phase separation (Banjade and Rosen, 2014) . With the expansion of SH3s and their potential partners came a requirement for higher specificity in their interactions (Kelil, Levy and Michnick, 2016) .…”