Structural origins of misfolding propensity in the platelet adhesive von Willebrand factor A1 domain. Biophys J 2015 Jul 21;109(2):398-406
Date
07/23/2015Pubmed ID
26200876Pubmed Central ID
PMC4621621DOI
10.1016/j.bpj.2015.06.008Scopus ID
2-s2.0-84937578847 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
The von Willebrand factor (VWF) A1 and A3 domains are structurally isomorphic yet exhibit distinct mechanisms of unfolding. The A1 domain, responsible for platelet adhesion to VWF in hemostasis, unfolds through a molten globule intermediate in an apparent three-state mechanism, while A3 unfolds by a classical two-state mechanism. Inspection of the sequences or structures alone does not elucidate the source of this thermodynamic conundrum; however, the three-state character of the A1 domain suggests that it has more than one cooperative substructure yielding two separate unfolding transitions not present in A3. We investigate the extent to which structural elements contributing to intermediate conformations can be identified using a residue-specific implementation of the structure-energy-equivalence-of-domains algorithm (SEED), which parses proteins of known structure into their constituent thermodynamically cooperative components using protein-group-specific, transfer free energies. The structural elements computed to contribute to the non-two-state character coincide with regions where Von Willebrand disease mutations induce misfolded molten globule conformations of the A1 domain. This suggests a mechanism for the regulation of rheological platelet adhesion to A1 based on cooperative flexibility of the α2 and α3 helices flanking the platelet GPIbα receptor binding interface.
Author List
Zimmermann MT, Tischer A, Whitten ST, Auton MAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AlgorithmsModels, Molecular
Mutation
Protein Folding
Protein Structure, Tertiary
Thermodynamics
von Willebrand Factor