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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2014, Vol. 8 Issue (1) : 6-16     DOI: 10.1007/s11684-014-0317-3
REVIEW |
Talin and kindlin: the one-two punch in integrin activation
Feng Ye(), Adam K. Snider, Mark H. Ginsberg()
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Abstract  

Proper cell-cell and cell-matrix contacts mediated by integrin adhesion receptors are important for development, immune response, hemostasis and wound healing. Integrins pass trans-membrane signals bidirectionally through their regulated affinities for extracellular ligands and intracellular signaling molecules. Such bidirectional signaling by integrins is enabled by the conformational changes that are often linked among extracellular, transmembrane and cytoplasmic domains. Here, we review how talin-integrin and kindlin-integrin interactions, in cooperation with talin-lipid and kindlin-lipid interactions, regulate integrin affinities and how the progress in these areas helps us understand integrin-related diseases.

Keywords signal transduction      transmembrane domain      nanodisc      integrin      talin      kindling      cell adhesion     
Corresponding Authors: Ye Feng,Email:feye@ucsd.edu; Ginsberg Mark H.,Email:mhginsberg@ucsd.edu   
Issue Date: 26 April 2014
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0317-3     OR     http://academic.hep.com.cn/fmd/EN/Y2014/V8/I1/6
Fig.1  Structure of integrin αIIbβ3 TMD (ribbon view; αIIb in red and β3 in blue. From PDB 2K9J) showing the two interaction interfaces. Left, outer membrane clasp (OMC). Right, inner membrane clasp (IMC). The important residues for the two interfaces are indicated.
Fig.2  Snorkeling Lys716 fixes the tilting angle of the β3 TMD. On the left, the C of Lys716 resides in the hydrophobic core but its ?-NH group snorkels into the negatively charged phosphate head group region. On the right, when Lys716 is mutated to Glu, the residue shifts away from hydrophobic core to place the side chain -COO group in the aqueous region. This shift causes reduced embedding of β3 TMD and decreased β3 TMD tilting angle.
Fig.3  Talin activates integrin by causing a topology change in β3 TMD. (A) Talin stabilizes the helix in the membrane proximal region of β3 and increases the tilting angle of the continuous β3 TMD. (B) A711P mutation introduces a flexible kink that breaks the continuous β3 TMD, decouples the tilting motion of the two helices, and blocks integrin activation.
Fig.4  Model for talin and kindlin function. Talin promotes affinity increase of individual integrin molecules. Kindlins have little primary effect on affinity of individual integrin but increase multivalent ligand binding by promoting the clustering of talin-activated αIIbβ3.
Fig.5  The dynamic equilibrium of integrin activation functions as signal integrator. The factors that shift the equilibrium to the same direction can add to or synergize with each other. Opposing factors can cancel each other.
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