Multiscale simulations suggest a mechanism for integrin inside-out activation.
Proc Natl Acad Sci U S A
; 108(29): 11890-5, 2011 Jul 19.
Article
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| MEDLINE
| ID: mdl-21730166
ABSTRACT
Integrins are large cell-surface adhesion receptors that can be activated to a high affinity state by the formation of an intracellular complex between the integrin ß-subunit tail, the membrane, and talin. The F2 and F3 subdomains of the talin head play a key role in formation of this complex. Here, activation of the integrin αIIb/ß3 dimer by the talin head domain was probed using multiscale molecular dynamics simulations. A number of novel insights emerge from these studies, including (i) the importance of the integrin αIIb subunit F992 and F993 residues in stabilizing the "off" state of the αIIb/ß3 dimer, (ii) a crucial role for negatively charged groups in the F2-F3/membrane interaction, (iii) binding of the talin F2-F3 domain to negatively charged lipid headgroups in the membrane induces a reorientation of the ß transmembrane (TM) domain, (iv) an increase in the tilt angle of the ß TM domain relative to the bilayer normal helps to destabilize the α/ß TM interaction and promote a scissor-like movement of the integrin TM helices. These results, combined with various published experimental observations, suggest a model for the mechanism of inside-out activation of integrins by talin.
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MEDLINE
Asunto principal:
Modelos Moleculares
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Membrana Celular
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Talina
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Glicoproteína IIb de Membrana Plaquetaria
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Integrina beta3
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Complejos Multiproteicos
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2011
Tipo del documento:
Article