Logic and Mechanism of an Evolutionarily Conserved Interaction in PDZ Domain

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Title: Logic and Mechanism of an Evolutionarily Conserved Interaction in PDZ Domain
Author: Sharma, Rohit
Abstract: Proteins are beautiful materials evolved to channel specific energetic perturbations into particular functions . At the core of virtually every biological process are two features of a protein : the energetic architecture and the mechanisms of energy propagation . Structural , dynamics , and mutagenesis experiments have revealed that anisotropy and cooperativity are common features of the energy propagation in proteins ; however , a complete understanding of the patterns and mechanisms of energy propagation remain unclear from these studies . Previous work in our lab developed a methodology , termed the Statistical Coupling Analysis (SCA ) , to estimate energetic interactions between residues in a protein from their statistical co -variation through evolution . The results of this algorithm revealed a small subset of the residues in a protein have significant energetic interactions and form a connected substructure in proteins and show excellent agreement with mutagenesis data in several systems . Using the same fundamental concepts of the original SCA , we have developed an improved version of SCA . This new algorithm provides , for the first time , a global map of the co -evolutionary interactions between residues in a protein from a multiple sequence alignment . The results of the new SCA are consistent with the original method but produce values for all pairs of positions . We then used the energetic map provided by SCA to understand the physical basis of specificity in the PDZ domain . The co -evolutionary energetic map of the PDZ domain predicts a long range interaction between position 372 , a known specificity determinant that directly interacts with ligand , and position 322 . Thermodynamic measurements in one PDZ domain reveal that position 322 modulates the specificity -determining interaction between 372 and its ligand contact . Structural studies show that flexibility at 322 is tuned to make conformational change on one side of the binding pocket sensitive to interactions at the distant specificity -determining contact . This designed mechanical coupling allows the domain to have AND gate -like behavior in screening for specific binding interactions . Understanding the logic and mechanism of a co -evolved interaction gives confidence in the ability of SCA to identify the functionally critical interactions in a protein , even when not structurally obvious . Given the functional and structural relevance of SCA predictions , we next addressed the topology of the energetic map in proteins . Analysis of several structurally and functionally diverse proteins revealed several common striking features in their energetic maps . First , the highly co -evolved positions in a protein show a high degree of mutual co -evolution so that , together , they form a nearly completely co -evolved sub -cluster . Secondly , the pattern of energetic interactions in proteins is highly heterogeneous , and fit a power -law distribution where most residues have very few co -evolutionary links with other residues and a few residues have many co -evolutionary links . The data is very consistent with extensive mutagenesis studies in several systems . Together , these experiments begin to demonstrate that the contiguous networks identified by SCA reflect structural regions capable of cooperatively channeling energy to produce functionality .
URI: http : / /hdl .handle .net /2152 .5 /670
Date: 2006-05-15

Citation

Logic and Mechanism of an Evolutionarily Conserved Interaction in PDZ Domain. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /670 .

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