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Structural basis of kindlin-mediated integrin recognition and activation.


ABSTRACT: Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain-containing proteins, talins and kindlins, respectively, bind different regions of ?-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically enhance their activation by talins. Here, we determined crystal structures of kindlin2 in the apo-form and the ?1- and ?3-integrin bound forms. The apo-structure shows an overall architecture distinct from talins. The complex structures reveal a unique integrin recognition mode of kindlins, which combines two binding motifs to provide specificity that is essential for integrin activation and signaling. Strikingly, our structures uncover an unexpected dimer formation of kindlins. Interrupting dimer formation impairs kindlin-mediated integrin activation. Collectively, the structural, biochemical, and cellular results provide mechanistic explanations that account for the effects of kindlins on integrin activation as well as for how kindlin mutations found in patients with Kindler syndrome and leukocyte-adhesion deficiency may impact integrin-mediated processes.

SUBMITTER: Li H 

PROVIDER: S-EPMC5584418 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Structural basis of kindlin-mediated integrin recognition and activation.

Li Huadong H   Deng Yi Y   Sun Kang K   Yang Haibin H   Liu Jie J   Wang Meiling M   Zhang Zhang Z   Lin Jirong J   Wu Chuanyue C   Wei Zhiyi Z   Yu Cong C  

Proceedings of the National Academy of Sciences of the United States of America 20170724 35


Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain-containing proteins, talins and kindlins, respectively, bind different regions of β-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically  ...[more]

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