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  • The EMBO Journal (2001) 20, 340 - 349
  • doi:10.1093/emboj/20.3.340

The extracellular human melanoma inhibitory activity (MIA) protein adopts an SH3 domain-like fold

Raphael Stoll1, Christian Renner1, Markus Zweckstetter1, Michael Brüggert1, Dorothee Ambrosius2, Stefan Palme2, Richard A. Engh2, Michaela Golob3, Ines Breibach3, Reinhard Buettner3, Wolfgang Voelter4, Tad A. Holak1 and Anja-Katrin Bosserhoff3

  1. Max Planck Institute of Biochemistry, D-82152 München, Germany
  2. Roche Diagnostics GmbH, Pharmaceutical Research, D-82377 Penzberg, Germany
  3. University Hospital of RWTH Aachen, Institute of Pathology, D-52074 Aachen, Germany
  4. Tübingen University, Department of Physical Biochemistry, Institute of Physiological Chemistry, D-72076 Tübingen, Germany

Correspondence to:

Tad A. Holak, E-mail: holak@biochem.mpg.de

Anja-Katrin Bosserhoff, E-mail: bosserhoff@pat.rwth-aachen.de

Received 7 July 2000; Accepted 12 December 2000; Revised 11 December 2000

Melanoma inhibitory activity (MIA) protein is a clinically valuable marker in patients with malignant melanoma, as enhanced values diagnose metastatic melanoma stages III and IV. Here we show that the recombinant human MIA adopts an SH3 domain-like fold in solution, with two perpendicular, antiparallel, three- and five-stranded beta-sheets. In contrast to known structures with the SH3 domain fold, MIA is a single-domain protein, and contains an additional antiparallel beta-sheet and two disulfide bonds. MIA is also the first extracellular protein found to have the SH3 domain-like fold. Furthermore, we show that MIA interacts with fibronectin and that the peptide ligands identified for MIA exhibit a matching sequence to type III human fibronectin repeats, especially to FN14, which is close to an integrin alpha4beta1 binding site. The present study, therefore, may explain the role of MIA in metastasis in vivo, and supports a model in which the binding of human MIA to type III repeats of fibronectin competes with integrin binding, thus detaching cells from the extracellular matrix.

  • Keywords:

    • extracellular SH3 domain,
    • fibronectin,
    • melanoma,
    • MIA,
    • NMR