The extracellular human melanoma inhibitory activity (MIA) protein adopts an SH3 domain-like fold.
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.
Stoll
R
R
Max Planck Institute of Biochemistry, D-82152 München, Germany.
Renner
C
C
Zweckstetter
M
M
Brüggert
M
M
Ambrosius
D
D
Palme
S
S
Engh
R A
RA
Golob
M
M
Breibach
I
I
Buettner
R
R
Voelter
W
W
Holak
T A
TA
Bosserhoff
A K
AK
D000595:Amino Acid Sequence; D001665:Binding Sites; D016326:Extracellular Matrix Proteins; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018909:src Homology Domains
D016326:Extracellular Matrix Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D019151:Peptide Library; D011994:Recombinant Proteins