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Journal Papers
Arnaout, M. A., Goodman, S. L. & Xiong, J.-P. Structure and mechanics of integrin-based cell adhesion. Curr. Opin. Cell Biol. 19, 495–507 (2007)
Meshel, A. S., Wei, Q., Adelstein, R. S. & Sheetz, M. P. Basic mechanism of three-dimensional collagen fibre transport by fibroblasts. Nat. Cell Biol. 7, 157–164 (2005)
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Outline
Introduction (integrins) Structure Ligand binding Conformational regulation Inside-out activation Example
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Introduction
Adhesion by integrins Binds to extracellular matrix (ECM)
through large ectodomain Binds to cytoskeleton through short
cytoplasmic tail
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Introduction
Adhesion by integrins Major role in organization of
tissue/organs Cytoskeleton controls affinity of
ectodomain to ECM (inside-out) ECM binding changes cytoskeleton
(outside-in) Transmission of force across
membrane
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Structure
Components 18 α-subunits 8 β-subunits Total of 24 integrins
2 groups Containing or Lacking von Willebrand
factor type A domain (αA)
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Structure
von Willebrand factor type A domain (αA) GTPase-like domain with a metal-ion-
dependent adhesion site (MIDAS) instead of the catalytic site
Closed (low affinity) or Open (high affinity) conformations
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Conformational regulation
Similarly to αA, βA affinity is assumed to be controlled by conformational change
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Conformational regulation
Switchblade model High affinity of βA
dependent on large Hybrid swing-out (~80°)
To provide space, knees fully extended
Allows access to binding site
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Conformational regulation
Deadbolt model High affinity of βA
possible with small changes between βTD and βA/Hybrid
Ligand binding provides energy for Hybrid swing-out (maybe knees not fully extended)
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Conformational regulation
Ligand-relay model Active βA changes conformation of αA
for high affinity αA is the ligand for βA
Consistent with deadbolt model
αA-containing αA-lacking
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Inside-out activation
Talin Actin binding protein Localized early with
high-affinity integrins Interaction β
Tail Close to membrane
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Inside-out activation
Talin Interaction close to
membrane Disrupts ionic bonds
between α and β tails Separation between
tails for inside-out activation
Unclear!
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Inside-out activation
Filamin Binds competitively with talin to β tails
Negatively regulates talin-induced activation
Calcium and integrin binding protein 1 (CIB1) Binds to αIIb peptide close to membrane
Potentially negatively regulates talin-induced activation
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Example
Collagen fiber transport by fibroblast Hand-over-hand cycle
Extension of lamellipodia Collagen bound by integrin Retraction of lamellipodia Collagen released