2q91

Publication Abstract from PubMed

S100A4, also known as mts1, is a member of the S100 family of Ca (2+)-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 Ca (2+) 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 Ca (2+) modifies the overall organization and structure of the protein, we determined the 1.7 A crystal structure of the human Ca (2+)-S100A4. Ca (2+) 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 Ca (2+)-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 Ca (2+) 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 Ca (2+)-S100A4. Most of these residues are not exposed in apo-S100A4 and explain the Ca (2+) dependence of formation of the S100A4-MIIA complex. These studies provide the foundation for understanding S100A4 target recognition and may support the development of reagents that interfere with S100A4 function.

Structure of Ca(2+)-Bound S100A4 and Its Interaction with Peptides Derived from Nonmuscle Myosin-IIA.,Malashkevich VN, Varney KM, Garrett SC, Wilder PT, Knight D, Charpentier TH, Ramagopal UA, Almo SC, Weber DJ, Bresnick AR Biochemistry. 2008 May 6;47(18):5111-5126. Epub 2008 Apr 15. PMID:18410126^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.