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Integrin extension enables ultrasensitive regulation by cytoskeletal force

Integrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational s... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 02 May 2017, Vol.114(18), pp.4685-4690
Main Author: Li, Jing
Other Authors: Springer, Timothy A
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; PMID: 28416675 Version:1 ; DOI: 10.1073/pnas.1704171114
Link: http://pubmed.gov/28416675
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recordid: medline28416675
title: Integrin extension enables ultrasensitive regulation by cytoskeletal force
format: Article
creator:
  • Li, Jing
  • Springer, Timothy A
subjects:
  • Adaptor
  • Cytoskeletal Force
  • Integrin Activation
  • Models, Biological
  • Cytoskeleton -- Metabolism
  • Integrins -- Metabolism
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 02 May 2017, Vol.114(18), pp.4685-4690
description: Integrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational state on the cell surface, together with the length scales of conformational change, are used to quantitatively compare models of activation. We examine whether binding of cytoskeletal adaptors to integrin cytoplasmic domains is sufficient for activation or whether exertion of tensile force by the actin cytoskeleton across the integrin-ligand complex is also required. We find that only the combination of adaptor binding and cytoskeletal force provides ultrasensitive regulation. Moreover, switch-like activation by force depends on the large, >130 Å length-scale change in integrin extension, which is well tailored to match the free-energy difference between the inactive (bent-closed) and active (extended-open) conformations. The length scale and energy cost in integrin extension enable activation by force in the low pN range and appear to be the key specializations that enable cell adhesion through integrins to be coordinated with cytoskeletal dynamics.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; PMID: 28416675 Version:1 ; DOI: 10.1073/pnas.1704171114
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleIntegrin extension enables ultrasensitive regulation by cytoskeletal force
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subjectAdaptor ; Cytoskeletal Force ; Integrin Activation ; Models, Biological ; Cytoskeleton -- Metabolism ; Integrins -- Metabolism
descriptionIntegrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational state on the cell surface, together with the length scales of conformational change, are used to quantitatively compare models of activation. We examine whether binding of cytoskeletal adaptors to integrin cytoplasmic domains is sufficient for activation or whether exertion of tensile force by the actin cytoskeleton across the integrin-ligand complex is also required. We find that only the combination of adaptor binding and cytoskeletal force provides ultrasensitive regulation. Moreover, switch-like activation by force depends on the large, >130 Å length-scale change in integrin extension, which is well tailored to match the free-energy difference between the inactive (bent-closed) and active (extended-open) conformations. The length scale and energy cost in integrin extension enable activation by force in the low pN range and appear to be the key specializations that enable cell adhesion through integrins to be coordinated with cytoskeletal dynamics.
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abstractIntegrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational state on the cell surface, together with the length scales of conformational change, are used to quantitatively compare models of activation. We examine whether binding of cytoskeletal adaptors to integrin cytoplasmic domains is sufficient for activation or whether exertion of tensile force by the actin cytoskeleton across the integrin-ligand complex is also required. We find that only the combination of adaptor binding and cytoskeletal force provides ultrasensitive regulation. Moreover, switch-like activation by force depends on the large, >130 Å length-scale change in integrin extension, which is well tailored to match the free-energy difference between the inactive (bent-closed) and active (extended-open) conformations. The length scale and energy cost in integrin extension enable activation by force in the low pN range and appear to be the key specializations that enable cell adhesion through integrins to be coordinated with cytoskeletal dynamics.
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