Tests of the extension and deadbolt models of integrin activation. J Biol Chem 2007 Apr 20;282(16):11914-20
Date
02/16/2007Pubmed ID
17301049Pubmed Central ID
PMC1952534DOI
10.1074/jbc.M700249200Scopus ID
2-s2.0-34249685565 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
Despite extensive evidence that integrin conformational changes between bent and extended conformations regulate affinity for ligands, an alternative hypothesis has been proposed in which a "deadbolt" can regulate affinity for ligand in the absence of extension. Here, we tested both the deadbolt and the extension models. According to the deadbolt model, a hairpin loop in the beta3 tail domain could act as a deadbolt to restrain the displacement of the beta3 I domain beta6-alpha7 loop and maintain integrin in the low affinity state. We found that mutating or deleting the beta3 tail domain loop has no effect on ligand binding by either alphaIIbbeta 3 or alphaVbeta3 integrins. In contrast, we found that mutations that lock integrins in the bent conformation with disulfide bonds resist inside-out activation induced by cytoplasmic domain mutation. Furthermore, we demonstrated that extension is required for accessibility to fibronectin but not smaller fragments. The data demonstrate that integrin extension is required for ligand binding during integrin inside-out signaling and that the deadbolt does not regulate integrin activation.
Author List
Zhu J, Boylan B, Luo BH, Newman PJ, Springer TAAuthor
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCHO Cells
Cell Membrane
Cricetinae
Cricetulus
Fibronectins
Humans
Integrin alphaV
Integrin beta3
Integrins
Ligands
Mutation
Platelet Membrane Glycoprotein IIb
Protein Binding
Protein Structure, Tertiary
