Insights into the structure and domain flexibility of full-length pro-matrix metalloproteinase-9/gelatinase B.
The multidomain zinc endopeptidase matrix metalloproteinase-9 (MMP-9) is a recognized therapeutic target in autoimmune diseases, vascular pathologies, and cancer. Despite its importance, structural characterization of full-length pro-MMP-9 is incomplete. Here, we report the structural model of full-length pro-MMP-9 and, in particular, the molecular character of its unique proline-rich and heavily O-glycosylated (OG) domain. Using a powerful combination of small-angle X-ray scattering and single-molecule imaging, we demonstrate that pro-MMP-9 possesses an elongated structure with two terminal globular domains connected by an unstructured OG domain. Image analysis highlights the flexibility of the OG domain, implicating its role in the varied enzyme conformations and in facilitating independent movements of the terminal domains. This may endorse recognition, binding, and processing of substrates, ligands, as well as receptors and marks this domain as an additional target for the design of selective regulators.
Rosenblum
Gabriel
G
Department of Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Van den Steen
Philippe E
PE
Cohen
Sidney R
SR
Grossmann
J Günter
JG
Frenkel
Jessica
J
Sertchook
Rotem
R
Slack
Nelle
N
Strange
Richard W
RW
Opdenakker
Ghislain
G
Sagi
Irit
I
D004792:Enzyme Precursors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
D004792:Enzyme Precursors; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9