Abstract
ABSTRACTWe have studied the mobility of the multidomain folding catalyst, protein disulfide isomerase (PDI), by a coarse‐graining approach based on flexibility. We analyze our simulations of yeast PDI (yPDI) using measures of backbone movement, relative positions and orientations of domains, and distances between functional sites. We find that there is interdomain flexibility at every interdomain junction but these show very different characteristics. The extent of interdomain flexibility is such that yPDI's two active sites can approach much more closely than is found in crystal structures—and indeed hinge motion to bring these sites into proximity is the lowest energy normal mode of motion of the protein. The flexibility predicted for yPDI (based on one structure) includes the other known conformation of yPDI and is consistent with (i) the mobility observed experimentally for mammalian PDI and (ii) molecular dynamics. We also observe intradomain flexibility and clear differences between the domains in their propensity for internal motion. Our results suggest that PDI flexibility enables it to interact with many different partner molecules of widely different sizes and shapes, and highlights considerable similarities of yPDI and mammalian PDI. Proteins 2016; 84:1776–1785. © 2016 Wiley Periodicals, Inc.
Highlights
Proteins show internal mobility over a wide range of time- and length-scales, from the rapid local motions that define the conformational entropy of a given protein conformation (ms) of loops or whole domains that interconvert different conformations.[1,2] The quantitative exploration of mobility across these vast timescales is important in order to understand the function of proteins, but remains a major challenge—both for proteins in isolation and in response to interactions with partner proteins and other molecules.One of the large proteins studied intensely is protein disulfide isomerase (PDI), an abundant catalyst of oxidative protein folding in the endoplasmic reticulum of secretory cells (Fig. 1)
Motion along the positive direction of m10, converts the relative orientation of the a and b domains into precisely that found in the alternative “high-temperature” crystal structure of yeast PDI (yPDI)
The X-ray work, based on yPDI crystals grown at different temperatures, has provided two structures which differ very little in the relative orientation of the b0 and a0 domains, but show clear differences in the N-terminal half of the protein, in the relative orientation of the a and b domains.[9,18]
Summary
Proteins show internal mobility over a wide range of time- and length-scales, from the rapid local motions that define the conformational entropy of a given protein conformation (ms) of loops or whole domains that interconvert different conformations.[1,2] The quantitative exploration of mobility across these vast timescales is important in order to understand the function of proteins, but remains a major challenge—both for proteins in isolation and in response to interactions with partner proteins and other molecules. One of the large proteins studied intensely is protein disulfide isomerase (PDI), an abundant catalyst of oxidative protein folding in the endoplasmic reticulum of secretory cells (Fig. 1).
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