title: A push-pull mechanism for regulating integrin function.
abstract: Homomeric and heteromeric interactions between the alphaIIb and beta3 transmembrane domains are involved in the regulation of integrin alphaIIbbeta3 function. These domains appear to interact in the inactivated state but separate upon integrin activation. Moreover, homomeric interactions may increase the level of alphaIIbbeta3 activity by competing for the heteromeric interaction that specifies the resting state. To test this model, a series of mutants were examined that had been shown previously to either enhance or disrupt the homomeric association of the alphaIIb transmembrane domain. One mutation that enhanced the dimerization of the alphaIIb transmembrane domain indeed induced constitutive alphaIIbbeta3 activation. However, a series of mutations that disrupted homodimerization also led to alphaIIbbeta3 activation. These results suggest that the homo- and heterodimerization motifs overlap in the alphaIIb transmembrane domain, and that mutations that disrupt the alphaIIb/beta3 transmembrane domain heterodimer are sufficient to activate the integrin. The data also imply a mechanism for alphaIIbbeta3 regulation in which the integrin can be shifted from its inactive to its active state by destabilizing an alphaIIb/beta3 transmembrane domain heterodimer and by stabilizing the resulting alphaIIb and beta3 transmembrane domain homodimers.
authors.affiliation: Department of Medicine, Hematology-Oncology Division, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Metcalf
authors.forename: Roman
authors.initials: R
authors.lastname: Gorelik
authors.forename: Renhao
authors.initials: R
authors.lastname: Li
authors.forename: Neal
authors.initials: N
authors.lastname: Mitra
authors.forename: Vikas
authors.initials: V
authors.lastname: Nanda
authors.forename: Peter B
authors.initials: PB
authors.lastname: Law
authors.forename: James D
authors.initials: JD
authors.lastname: Lear
authors.forename: William F
authors.initials: WF
authors.lastname: Degrado
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bennett
mesh_terms: D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D019281:Dimerization; D007150:Immunohistochemistry; D039661:Integrin beta3 / Q000378:metabolism / Q000502:physiology*; D008958:Models, Molecular; D016296:Mutagenesis; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb; D011994:Recombinant Proteins