The dual structural roles of the membrane distal region of the ?-integrin cytoplasmic tail during integrin inside-out activation.

ABSTRACT: Studies on the mechanism of integrin inside-out activation have been focused on the role of ?-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for ?-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the ?-integrin membrane-proximal region to keep the integrin inactive. The ?-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the ?-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation. Complete deletion of the ?-integrin membrane-distal region diminished talin- and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in ?-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the ?-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

SUBMITTER: Liu J 

PROVIDER: S-EPMC6518327 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature