MT1-MMP Binds Membranes by Opposite Tips of Its β Propeller to Position It for Pericellular Proteolysis

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2018 Nov 26

PMID 30471921

Citations 8

Authors

Tara C Marcink

Jayce A Simoncic

Bo An

Anna M Knapinska

Yan G Fulcher

Narahari Akkaladevi

Gregg B Fields

Steven R Van Doren

Affiliations

Soon will be listed here.

Abstract

Critical to migration of tumor cells and endothelial cells is the proteolytic attack of membrane type 1 matrix metalloproteinase (MT1-MMP) upon collagen, growth factors, and receptors at cell surfaces. Lipid bilayer interactions of the substrate-binding hemopexin-like (HPX) domain of MT1-MMP were investigated by paramagnetic nuclear magnetic resonance relaxation enhancements (PREs), fluorescence, and mutagenesis. The HPX domain binds bilayers by blades II and IV on opposite sides of its β propeller fold. The EPGYPK sequence protruding from both blades inserts among phospholipid head groups in PRE-restrained molecular dynamics simulations. Bilayer binding to either blade II or IV exposes the CD44 binding site in blade I. Bilayer association with blade IV allows the collagen triple helix to bind without obstruction. Indeed, vesicles enhance proteolysis of collagen triple-helical substrates by the ectodomain of MT1-MMP. Hypothesized side-by-side MT1-MMP homodimerization would allow binding of bilayers, collagen, CD44, and head-to-tail oligomerization.

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