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A molecular switch ‐ insights into allosteric control of vinculin function from in‐silico study of its large‐scale conformational dynamics
Author(s) -
Chen Yiwen,
Dokholyan Nikolay V.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a270
Subject(s) - vinculin , allosteric regulation , molecular dynamics , chemistry , biophysics , conformational change , in silico , dynamics (music) , protein dynamics , ferm domain , computational biology , cell adhesion , biochemistry , biology , cell , enzyme , physics , computational chemistry , membrane protein , integral membrane protein , membrane , gene , acoustics
Vinculin is a 117kDa protein that is comprised of five helix bundle domains. It is an important constituent of both cell‐cell and cell‐matrix junctions, where it plays crucial roles in the regulation of cell adhesion and migration. It is established that the activation of vinculin requires significant conformational changes from an auto‐inhibited conformation to the “open” conformations in which the cryptic binding sites of different ligands become exposed. However, the conformational dynamics underlying the vinculin activation remains largely unknown. Here we report the first computational study of large‐scale conformational dynamics of full‐length vinculin using the state‐of‐art discrete molecular dynamics (DMD) method. Our simulations uncover the structural and dynamic basis of vinculin activation from both thermodynamic and kinetic perspectives, and reveal distinct and complementary roles of internal (flexibility, domain‐domain interaction within vinculin) and external (talin binding) factors in allosteric control of vinculin. This work was published ( Journal of Biological Chemistry , 281 : 29148ndash;29154, (2006)), and supported in part by Muscular Dystrophy Association Grant MDA3720, American Heart Association Grant 0665361U, and North Carolina Biotechnology Center Grant 2006‐MRG‐1107 (to N. V. D.)