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J. Biol. Chem., Vol. 277, Issue 42, 39899-39908, October 18, 2002
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IIb
3
From the Departamento de Biofísica Molecular, Instituto de
Química Física, Consejo Superior de Investigaciones
Científicas, Serrano 119, E-28006 Madrid, Spain
Concrete structural features of integrin
IIb
3 on the surface of platelets
(at rest and after activation) have been obtained from epitope maps
based on cross-competition among monoclonal antibodies directed against
the IIb subunit calf-2 domain and the
3 subunit A domain of
IIb3. At rest, the observed intersubunit interface is formed by the sequence stretches
3-(150-216), IIb light chain-(1-92),
and IIb heavy chain-(826-856); and the
IIb interchain interface is formed by the two latter
sequence stretches, disulfide-bonded between IIb heavy
chain Cys826 and IIb light chain
Cys9. These structural features agree with those observed
in the IIb3 rudimentary connectivity map
in solution and with the v3 V-shaped crystal structure (Xiong, J.-P., Zhang, R., Dunker, R., Scott, D. L., Joachimiak, A., Goodman, S. L., and Arnaout, M. A. (2001) Science 294, 339-345), but they disagree with
the domain disposition suggested by the actual ultrastructural model.
The epitope maps in platelets activated by ADP, thrombin receptor
activation peptide, and arachidonic acid differ not only from those in
platelets at rest, but also among themselves. The structural
rearrangements observed confirm the presence in activated platelets of
the crystallographically observed knee and argue against the
switchblade mechanism proposed for activation (Beglova, N., Blacklow,
S. C., Takagi, J., and Springer, T. A. (2002) Nat.
Struct. Biol. 9, 282-287), demonstrate the existence of
IIb3 agonist-specific activation states,
explain the specificity for ligand binding and functional inhibition
for some agonists, and predict the existence of agonist-specific final effectors and receptor activation mechanisms. The distinct
non-reciprocal competition patterns observed at rest and after
activation support the agonist-specific activation states and the
existence of intrasubunit and intersubunit allosteric effects,
previously proposed as the mechanism for
IIb3 transmembrane activation.
To whom correspondence should be addressed. Tel.: 34-1-561-9400;
Fax: 34-1-564-2431; E-mail: J.Gonzalez-Rodriguez@iqfr.csic.es.
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