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Title: Conformational selection in a protein-protein interaction revealed by dynamic pathway analysis

Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsin kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using NMR spectroscopy, stopped-flow kinetics and isothermal titration calorimetry we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Lastly, protein dynamics in free recoverin limits the overall rate of binding.
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [1]
  1. Howard Hughes Medical Inst., Chevy Chase, MD (United States); Brandeis Univ., Waltham, MA (United States)
  2. Univ. of Oxford, Oxford (United Kingdom)
  3. Paul Scherrer Inst. (PSI), Villigen (Switzerland)
  4. Brandeis Univ., Waltham, MA (United States)
Publication Date:
Grant/Contract Number:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 2211-1247
Research Org:
Brandeis Univ., Waltham, MA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; conformational selection; molecular recognition dynamics; protein/protein interaction; conformational ensemble; energy landscape; recoverin
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1239247