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A conserved sequence within the propeptide domain of membrane type 1 matrix metalloproteinase is critical for

Maria Pavlaki1, Jian Cao, Michelle Hymowitz

  • 1Department of Veterans Affairs Medical Center, Northport, New York 11768, USA.

The Journal of Biological Chemistry
|November 13, 2001
PubMed

Insights

A conserved YGYL sequence in MT1-MMP's propeptide is crucial for its intramolecular chaperone activity, enabling enzyme activation and cell surface functions. This sequence is vital for matrix metalloproteinase (MMP) function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Matrix metalloproteinases (MMPs) are enzymes involved in extracellular matrix degradation.
  • The propeptide domain of MMPs maintains enzyme latency.
  • Membrane type 1 matrix metalloproteinase (MT1-MMP) functions as an intramolecular chaperone.

Purpose of the Study:

  • To investigate the role of a conserved four-amino acid sequence (42)YGYL(45) in the MT1-MMP propeptide.
  • To determine if this sequence is essential for MT1-MMP's chaperone activity and function.

Main Methods:

  • Site-directed mutagenesis was used to create alanine substitution mutants of the (42)YGYL(45) sequence in MT1-MMP.
  • Mutant MT1-MMP cDNAs were transfected into COS-1 cells.
  • Immunofluorescence, proMMP-2 activation assays, TIMP-2 binding assays, and fibronectin degradation/migration assays were performed.

Main Results:

  • Mutant MT1-MMP proteins were synthesized and localized to the plasma membrane.
  • Alanine substitutions in the (42)YGYL(45) sequence impaired proMMP-2 activation and TIMP-2 binding.
  • Mutant MT1-MMP-expressing cells showed reduced fibronectin degradation and migration.

Conclusions:

  • The conserved (42)YGYL(45) sequence in MT1-MMP is essential for its intramolecular chaperone function.
  • This sequence is critical for MT1-MMP's enzymatic activity, substrate binding, and cell-mediated matrix degradation.

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