2Q91

Structure of the Ca2+-Bound Activated Form of the S100A4 Metastasis Factor

Summary for 2Q91

• Entry DOI: 10.2210/pdb2q91/pdb
• Descriptor: S100A4 Metastasis Factor, CALCIUM ION (3 entities in total)
• Functional Keywords: s100a4, myosin, calcium, metastatic tumors, ef-hand, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 23651.39

Authors

Malashkevich, V.N.,Knight, D.,Ramagopal, U.A.,Almo, S.C.,Bresnick, A.R. (deposition date: 2007-06-12, release date: 2008-02-26, Last modification date: 2024-02-21)

Primary citation

Malashkevich, V.N.,Varney, K.M.,Garrett, S.C.,Wilder, P.T.,Knight, D.,Charpentier, T.H.,Ramagopal, U.A.,Almo, S.C.,Weber, D.J.,Bresnick, A.R.
Structure of Ca(2+)-Bound S100A4 and Its Interaction with Peptides Derived from Nonmuscle Myosin-IIA.
Biochemistry, 47:5111-5126, 2008

PubMed Abstract: S100A4, also known as mts1, is a member of the S100 family of Ca2+-binding proteins that is directly involved in tumor invasion and metastasis via interactions with specific protein targets, including nonmuscle myosin-IIA (MIIA). Human S100A4 binds two Ca2+ ions with the typical EF-hand exhibiting an affinity that is nearly 1 order of magnitude tighter than that of the pseudo-EF-hand. To examine how Ca2+ modifies the overall organization and structure of the protein, we determined the 1.7 A crystal structure of the human Ca2+-S100A4. Ca2+ binding induces a large reorientation of helix 3 in the typical EF-hand. This reorganization exposes a hydrophobic cleft that is comprised of residues from the hinge region,helix 3, and helix 4, which afford specific target recognition and binding. The Ca2+-dependent conformational change is required for S100A4 to bind peptide sequences derived from the C-terminal portion of the MIIA rod with submicromolar affinity. In addition, the level of binding of Ca2+ to both EF-hands increases by 1 order of magnitude in the presence of MIIA. NMR spectroscopy studies demonstrate that following titration with a MIIA peptide, the largest chemical shift perturbations and exchange broadening effects occur for residues in the hydrophobic pocket of Ca2+-S100A4. Most of these residues are not exposed in apo-S100A4 and explain the Ca2+ dependence of formation of theS100A4-MIIA complex. These studies provide the foundation for understanding S100A4 target recognition and may support the development of reagents that interfere with S100A4 function.

PubMed: 18410126
DOI: 10.1021/bi702537s

Experimental method

X-RAY DIFFRACTION (1.63 Å)