Protein Engineering, Vol 10, 1395-1405, Copyright © 1997 by Oxford University Press
TA Haas and EF Plow
The cytoplasmic tails of integrin heterodimers play central roles in
controlling the activation states of integrins and in transmitting
intracellular signals. Despite their short length, no structure of any
integrin cytoplasmic domain has been determined. Therefore, molecular
models for the cytoplasmic domain of alpha(IIb)beta3, the major platelet
integrin, were generated, including models for the individual cytoplasmic
tails, the binary alphaIIb-calcium complex, and the ternary
alphaIIb-beta3-calcium complex. Structural analysis of circular dichroism
spectra were compiled with data obtained from short homologous sequences
within crystallized proteins, and with secondary structural predictions to
develop starting models for each subunit. These models were subjected to a
series of energy minimization and molecular dynamic simulations to generate
final models. AlphaIIb was predicted to be ordered at its N-terminus and
its C-terminus could accommodate a cation in a multicoordinated complex.
The structure of beta3 was dominated by a beta-turn at its NPXY motif
(beta3 744-747). In docking of alphaIIb to different sites within beta3,
the conformation of the beta3 juxta-transmembrane (beta3 716-721) was
greatly altered. This region was confirmed to be a conformational 'hot-
spot' by circular dichroism. The conformational flexibility of this
juxta-transmembrane region, which is highly conserved amongst integrins, is
ideally located to regulate signaling.
ARTICLES
Development of a structural model for the cytoplasmic domain of an integrin
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic Foundation, OH 44195, USA.
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