Non-proteolytic, receptor/ligand interactions associate cellular membrane type-1 matrix metalloproteinase with the complement component C1q

Dmitri V. Rozanov, Sergey Sikora, Adam Godzik, Tatiana I. Postnova, Vladislav Golubkov, Alexei Savinov, Stephen Tomlinson, Alex Y. Strongin

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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 silica modeling followed by mutagenesis and the in vitro and cell-based binding studies showed that the His171-Glu-Lys-Gln-Ala-Asp176 and Val 223-Arg-Asn224 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.

Original languageEnglish (US)
Pages (from-to)50321-50328
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number48
DOIs
StatePublished - Nov 26 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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