Eugenia V. Gurevich
Vladimir N. Uversky
1 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA;
2 Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
3 Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, Russia 142290
Funds: NIH RO1 Grants EY011500, GM077561 and GM109955 (the latter two RO1s were replaced by R35 GM122491) (VVG), NS065868 and DA030103 (EVG).
Received Date: 2017-09-01
Rev Recd Date:2017-11-27
Abstract
Abstract
Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations:free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests that arrestins are no exception to this rule:their flexibility is necessary for functional versatility. The data on arrestins and many other multi-functional proteins indicate that in many cases, "order" might be artificially imposed by highly non-physiological crystallization conditions and/or crystal packing forces. In contrast, conformational flexibility (and its extreme case, intrinsic disorder) is a more natural state of proteins, representing true biological order that underlies their physiologically relevant functions.Keywords: arrestin,
GPCR,
crystal structure,
NMR,
EPR,
disorder,
protein-protein interactions
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