Proteolysis of the membrane type-1 matrix metalloproteinase prodomain: implications for a two-step proteolytic processing and activation.
Membrane type-1 matrix metalloproteinase (MT1-MMP) exerts its enhanced activity in multiple cancer types. Understanding the activation process of MT1-MMP is essential for designing novel and effective cancer therapies. Like all of the other MMPs, MT1-MMP is synthesized as a zymogen, the latency of which is maintained by its inhibitory prodomain. Proteolytic processing of the prodomain transforms the zymogen into a catalytically active enzyme. A sequential, two-step activation process is normally required for MMPs. Our in silico modeling suggests that the prodomain of MT1-MMP exhibits a conserved three helix-bundled structure and a "bait" loop region linking helixes 1 and 2. We hypothesized and then confirmed that in addition to furin cleavage there is also a cleavage at the bait region in the activation process of MT1-MMP. A two-step sequential activation of MT1-MMP is likely to include the MMP-dependent cleavage at either P47GD downward arrowL50 or P58QS downward arrowL61 or at both sites of the bait region. This event results in the activation intermediate. The activation process is then completed by a proprotein convertase cleaving the inhibitory prodomain at the R108RKR111 downward arrowY112 site, where Tyr112 is the N-terminal residue of the mature MT1-MMP enzyme. Our findings suggest that the most efficient activation results from a two-step mechanism that eventually is required for the degradation of the inhibitory prodomain and the release of the activated, mature MT1-MMP enzyme. These findings shed more light on the functional role of the inhibitory prodomain and on the proteolytic control of MT1-MMP activation, a crucial process that may be differentially regulated in normal and cancer cells.
Golubkov
Vladislav S
VS
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Chekanov
Alexei V
AV
Shiryaev
Sergey A
SA
Aleshin
Alexander E
AE
Ratnikov
Boris I
BI
Gawlik
Katarzyna
K
Radichev
Ilian
I
Motamedchaboki
Khatereh
K
Smith
Jeffrey W
JW
Strongin
Alex Y
AY
D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000737:chemistry / Q000201:enzymology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism
D004792:Enzyme Precursors; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14