TY - JOUR
T1 - Conversion between three conformational states of integrin I domains with a C-terminal pull spring studied with molecular dynamics
AU - Jin, Moonsoo
AU - Andricioaei, Ioan
AU - Springer, Timothy A.
N1 - Funding Information:
This work was supported by National Institutes of Health grants CA31798 and HL48675. We deeply appreciate contributions from Martin Karplus to this work.
PY - 2004/12
Y1 - 2004/12
N2 - We test with molecular dynamics the hypothesis that interdomain forces in integrins, simulated with a spring attached to the C-terminal α7-helix of an integrin I domain, can allosterically stabilize alternative I domain conformations. Depending on the force applied and timecourse, in αL and αM I domains the β6-α7 loop moves successively between three ratchet positions; i.e. from closed to intermediate, and then to open. More distal, linked alterations in MIDAS loops and metal coordination closely resemble those seen when the MIDAS becomes ligated. Simulations show that the intermediate state is populated over a wider range of forces for αL than αM I domains. Simulations with mutant I domains suggest that specific ratchet residues regulate conformational equilibria. Simulations with α1 and α2 I domains reveal a lack of the intermediate conformation, owing to Phe to Glu substitution at the second ratchet residue. The findings have important implications for biological regulation of integrin adhesiveness.
AB - We test with molecular dynamics the hypothesis that interdomain forces in integrins, simulated with a spring attached to the C-terminal α7-helix of an integrin I domain, can allosterically stabilize alternative I domain conformations. Depending on the force applied and timecourse, in αL and αM I domains the β6-α7 loop moves successively between three ratchet positions; i.e. from closed to intermediate, and then to open. More distal, linked alterations in MIDAS loops and metal coordination closely resemble those seen when the MIDAS becomes ligated. Simulations show that the intermediate state is populated over a wider range of forces for αL than αM I domains. Simulations with mutant I domains suggest that specific ratchet residues regulate conformational equilibria. Simulations with α1 and α2 I domains reveal a lack of the intermediate conformation, owing to Phe to Glu substitution at the second ratchet residue. The findings have important implications for biological regulation of integrin adhesiveness.
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U2 - 10.1016/j.str.2004.10.005
DO - 10.1016/j.str.2004.10.005
M3 - Article
C2 - 15576028
AN - SCOPUS:9944231967
VL - 12
SP - 2137
EP - 2147
JO - Structure
JF - Structure
SN - 0969-2126
IS - 12
ER -