The dual structural roles of the membrane distal region of the α-integrin cytoplasmic tail during integrin inside-out activation. J Cell Sci 2015 May 01;128(9):1718-31
Date
03/10/2015Pubmed ID
25749862Pubmed Central ID
PMC6518327DOI
10.1242/jcs.160663Scopus ID
2-s2.0-84929492742 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Studies on the mechanism of integrin inside-out activation have been focused on the role of β-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for α-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the β-integrin membrane-proximal region to keep the integrin inactive. The α-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 α-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation. Complete deletion of the α-integrin membrane-distal region diminished talin- and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in α-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the α-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.
Author List
Liu J, Wang Z, Thinn AM, Ma YQ, Zhu JAuthor
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCarrier Proteins
Cytoplasm
Humans
Integrin alpha Chains
Integrin beta3
K562 Cells
Mice
Mutant Proteins
Mutation
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Sequence Deletion
Structure-Activity Relationship
Talin
Tetradecanoylphorbol Acetate
