title: Structural basis for integrin alphaIIbbeta3 clustering.
abstract: We have expressed two proteins that correspond to the transmembrane and cytoplasmic domains of integrin alphaIIb and beta3 subunits. Characterization of these proteins, dispersed in anionic and zwitterionic micelles, revealed that, rather than interacting with each other, the two proteins associated into homodimers and homotrimers respectively. Moreover, studies using the TOXCAT assay system confirmed that the alphaIIb and beta3 transmembrane domains can self-associate in biological cell membranes. Transmembrane domain-mediated homo-oligomerization provides a plausible structural basis for integrin clustering and could promote integrin activation as well. Indeed, replacing specific residues in the transmembrane helix of either alphaIIb or beta3 with an asparagine residue resulted in a facilitated homo-oligomerization of the mutated transmembrane helix, promoted the formation of integrin clusters on the cell surface and shifted alphaIIbbeta3 to its activated state. Thus these studies support the hypothesis that the transmembrane domains play a vital role in the function and regulation of alphaIIbbeta3.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.forename: J S
authors.initials: JS
authors.lastname: Bennett
authors.forename: W F
authors.initials: WF
authors.lastname: Degrado
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D008024:Ligands; D008823:Micelles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D008024:Ligands; D008823:Micelles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex