Protein interactions and ligand binding: From protein subfamilies to functional specificity

Abstract

The divergence accumulated during the evolution of protein families translates into their internal organization as subfamilies, and it is directly reflected in the characteristic patterns of differentially conserved residues. These specifically conserved positions in protein subfamilies are known as "specificity determining positions" (SDPs). Previous studies have limited their analysis to the study of the relationship between these positions and ligandbinding specificity, demonstrating significant yet limited predictive capacity. We have systematically extended this observation to include the role of differential protein interactions in the segregation of protein subfamilies and explored in detail the structural distribution of SDPs at protein interfaces. Our results show the extensive influence of protein interactions in the evolution of protein families and the widespread association of SDPs with protein interfaces. The combined analysis of SDPs in interfaces and ligandbinding sites provides a more complete picture of the organization of protein families, constituting the necessary framework for a large scale analysis of the evolution of protein function.functional residues | protein family evolution | protein function | protein-protein interfaces | specificity determining positions T he structure of protein families is shaped by the sequence divergence accumulated as a consequence of speciation, gene duplication, and deletion events, as well as by the evolutionary selective pressure exerted on each protein in accordance with the corresponding 3D structure and the specific function performed (1, 2). The balance between genomic rearrangements and selective pressure to increase the functional repertoire available to organisms leads to the appearance of new subfamilies in evolutionary time (3).There are many aspects of protein function that contribute to the evolution of the family organization. These may include the global conservation of catalytic mechanisms (in the case of enzymes), specific binding to substrates and cofactors, as well as the interaction with other proteins in processes such as cell signaling, the regulation of reactions and the formation of macromolecular complexes. Interestingly, even though specific protein interactions certainly are an important part of protein function, the organization of protein families in relation to the specific interactions of different subfamilies remains a poorly studied aspect of functional specificity.Multiple sequences alignments (MSAs) provide essential information on the evolution of protein families. The positions in MSAs can be interpreted in terms of the amino acid changes allowed or disallowed during evolution, and therefore useful information at the residue level can be inferred from them (4). The most obvious example is the study of fully conserved positions that pinpoint important residues for the structure and function of the family members (5).A subtler pattern of conservation is represented by the positions differentially conserved within subfamili...

Strigolactone Promotes Degradation of DWARF14, an α/β Hydrolase Essential for Strigolactone Signaling inArabidopsis

“…Pro-169 is located in the external surface of the cap domain with the side chain exposed to the solvent, suggesting that the mutation affects critical proteinprotein interactions. This position is one of the seven SDPs (Rausell et al, 2010) found between D14 and KAI2 proteins, which have either conserved Pro or Ser, respectively, suggesting that these residues help determine the functional specificity of each protein type. It is also unlikely that they are involved in D14-MAX2 interactions, as both D14 and KAI2 seem to interact with MAX2, based on molecular and genetic evidence (Nelson et al, 2011;Hamiaux et al, 2012;Waters et al, 2012b;Kagiyama et al, 2013).…”

“…Sequence hits were further aligned with MUSCLE (Edgar, 2004). SDPs were analyzed with JDet (Muth et al, 2012) using the S3det method (Rausell et al, 2010) implemented in the JDet software. D14 (PDB:4ih4) and KAI2 (PDB:3w06) structures were aligned with FATCAT (Ye and Godzik, 2004).…”

Spatial Compartmentalization Specializes the Function of Aurora A and Aurora B

“…It is well accepted that duplication and divergence are the primary means by which new proteins and pathways are created. There are many factors including the substrate specificity, the specified binding of proteins, and the spatial mechanisms like the scaffolds, the regulation of reactions, and the formation of macromolecular complexes that contribute to the evolution and divergence of the proteins (22,23). Generally, fully conserved positions of proteins may confer the proteins' common functional features, whereas less conserved specificity-determining positions are related to their divergent functions.…”

Recognizing metal and acid radical ion-binding sites by integrating ab initio modeling with template-based transferals

“…Therefore, accurate identification of the protein-ion-binding sites is important for understanding the mechanism of protein function and for new drug discovery. Many computational methods have been proposed in the last two decades for predicting general ligand-protein binding sites, which can be roughly grouped into two categories of sequencebased (Capra and Singh, 2007;Chen et al, 2014Chen et al, , 2016Magliery and Regan, 2005;Rausell et al, 2010) and structure-based (Brylinski and Skolnick, 2008;Capra et al, 2009;Hendlich et al, 1997;Laskowski, 1995;Roche et al, 2011;Roy and Zhang, 2012;Wass et al, 2010;Yang et al, 2013b) approaches. The sequence-based methods mostly rely on residue conservation analyses under the assumption that ligand-binding residues are functionally important and therefore should be conserved in the evolution.…”