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J. Biol. Chem., Vol. 276, Issue 26, 24212-24222, June 29, 2001
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From the a Department of Molecular Cancer Biology, Danish
Cancer Society, Copenhagen DK-2100, Denmark, the c Department
of Biology, University of York, Heslington, d York Structural
Biology Centre, Department of Chemistry, University of York, York,
j YCR Cancer Research Unit, Department of Biology, University of
York, York YO10 5DD, United Kingdom, the g Institute of Mass
Spectrometry, Department of Chemistry, University of Warwick,
Coventry CV4 7AL, United Kingdom, and i National Institute
for Medical Research, Mill Hill, London NW7 1AA, United Kingdom
The S100 calcium-binding proteins are
implicated in signal transduction, motility, and cytoskeletal dynamics.
The three-dimensional structure of several S100 proteins revealed that
the proteins form non-covalent dimers. However, the mechanism of the
S100 dimerization is still obscure. In this study we characterized the
dimerization of S100A4 (also named Mts1) in vitro and
in vivo. Analytical ultracentrifugation revealed that
apoS100A4 was present in solution as a mixture of monomers and
dimers in a rapidly reversible equilibrium (Kd = 4 ± 2 µM). The binding of calcium
promoted dimerization. Replacement of Tyr-75 by Phe resulted in the
stabilization of the dimer. Helix IV is known to form the major part of
the dimerization interface in homologous S100 proteins. By using the
yeast two-hybrid system we showed that only a few residues of helix IV,
namely Phe-72, Tyr-75, Phe-78, and Leu-79, are essential for
dimerization in vivo. A homology model demonstrated that
these residues form a hydrophobic cluster on helix IV. Their role is to
stabilize the structure of individual subunits rather than provide
specific interactions across the dimerization surface. Our mutation
data showed that the specificity at the dimerization surface is not particularly stringent, which is consistent with recent data indicating that S100 proteins can form heterodimers.
The Dimerization Interface of the
Metastasis-associated Protein S100A4 (Mts1)
IN VIVO AND IN VITRO STUDIES*,
*
This work was supported in part by the Yorkshire Cancer
Research, the Danish Cancer Society, the Danish Medical Research
Council, the Novo Foundation, and the Danish Cancer Research
Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains Additional Materials.
b
Present address and to whom correspondence should be
addressed: Institute of Molecular Biology, Dept. of Molecular Cell
Biology, University of Copenhagen, Copenhagen 1353, Denmark. Tel.:
45-35-32-20-92; Fax: 45-33-93-52-20; E-mail: panina@hotmail.com.
e
Supported by the York Structural Biology Laboratory.
f
Supported by Molecular Simulation, Inc. Present address:
Center for Novel Agricultural Products, Dept. of Biology, University of
York, York, YO10 5DD, UK.
h
Royal Society University Research Fellow. Present address:
Protonic Nanomachine Project, ERATO, Japan Science and Technology Corp., 3-4 Hikaridai, Seika, Kyoto, Japan.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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