Non-proteolytic, receptor/ligand interactions associate cellular membrane type-1 matrix metalloproteinase with the complement component C1q.
Membrane type-1 matrix metalloproteinase (MT1-MMP), a prototypic member of the membrane-tethered MMP family, is an essential component of a cellular proteolysis apparatus. Recognition of protein cleavage targets followed by proteolysis is a main function of MT1-MMP. For the first time, however, we present evidence that MT1-MMP and other structurally related membrane MMPs bind C1q, the recognition unit of the first component of complement C1 that initiates activation of the classical pathway of complement. These interactions involve the catalytic domain of MT1-MMP and the C1q globular domain. In silico modeling followed by mutagenesis and the in vitro and cell-based binding studies showed that the His(171)-Glu-Lys-Gln-Ala-Asp(176) and Val(223)-Arg-Asn(224) peptide sequences of MT1-MMP are directly involved in the binding with C1q. These sequence regions are spatially distant from the active site of the protease. As a result, the catalytically active and the catalytically latent forms of cellular MT1-MMP are both efficient in binding with C1q. In agreement, despite the MT1-MMP/C1q interactions, C1q is totally resistant to MT1-MMP proteolysis. The discovery of the unconventional, receptor/ligand-like interactions of MT1-MMP with C1q, an essential component of immunity, is a significant step toward a more complete understanding of the role of this membrane-tethered protease in cancer.
Rozanov
Dmitri V
DV
Burnham Institute, La Jolla, California 92037, USA.
Sikora
Sergey
S
Godzik
Adam
A
Postnova
Tatiana I
TI
Golubkov
Vladislav
V
Savinov
Alexei
A
Tomlinson
Stephen
S
Strongin
Alex Y
AY
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism*; D015922:Complement C1q / Q000378:metabolism*; D019295:Computational Biology; D006801:Humans; D008024:Ligands; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016415:Sequence Alignment
D008024:Ligands; D015922:Complement C1q; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases