Abstract
Protein-protein interactions play important roles in the control of every cellular process. How natural selection has optimized protein design to produce molecules capable of binding to many partner proteins is a fascinating problem but not well understood. Here, we performed a combinatorial analysis of protein sequence evolution and conformational dynamics to study how calmodulin (CaM), which plays essential roles in calcium signaling pathways, has adapted to bind to a large number of partner proteins. We discovered that amino acid residues in CaM can be partitioned into unique classes according to their degree of evolutionary conservation and local stability. Holistically, categorization of CaM residues into these classes reveals enriched physico-chemical interactions required for binding to diverse targets, balanced against the need to maintain the folding and structural modularity of CaM to achieve its overall function. The sequence-structure-function relationship of CaM provides a concrete example of the general principle of protein design. We have demonstrated the synergy between the fields of molecular evolution and protein biophysics and created a generalizable framework broadly applicable to the study of protein-protein interactions.
Highlights
Protein-protein interactions play important roles in the control of every cellular process
Both aspects of protein design must have a degree of adaptability to adjust to pressures from evolutionary advances[3,4]. It remains elusive how a protein evolves under the selection constraint for versatility over stability in order to achieve a functionally optimized structure. This is a fundamental question for understanding the impact of evolutionary pressure on a protein sequence and how resulting mutations are tolerated or not in the face of meeting demands of conformational dynamics required for function[5,6,7]
Because CaM is optimized through evolution to bind to a multitude of diverse targets[4,20], we first determined the evolutionary conservation of its amino acid residues using the Evolutionary Tracer[21]
Summary
Protein-protein interactions play important roles in the control of every cellular process. Structural stability provides architectural framework while flexibility provides for adaptable surfaces or enzymatic sites to mediate function[2] Both aspects of protein design must have a degree of adaptability to adjust to pressures from evolutionary advances[3,4]. It remains elusive how a protein evolves under the selection constraint for versatility over stability in order to achieve a functionally optimized structure. We quantified the conformational dynamics in terms of local frustration of amino acids in CaM in 60 CaM/target complexes using the Frustratometer[22] With this unique combinatorial approach, we were able to separate CaM residues into novel discrete classes, bringing significant new insights of how evolution has optimized CaM to balance promiscuous binding behavior, while maintaining specificity
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