Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail.
Pericellular proteolysis represents one of the key modes by which the cell can modulate its environment, involving not only turnover of the extracellular matrix but also the regulation of cell membrane proteins, such as growth factors and their receptors. The metzincins are active players in such proteolytic events, and their mode of regulation is therefore of particular interest and importance. The TIMPs (tissue inhibitors of metalloproteinases) are established endogenous inhibitors of the matrix metalloproteinases (MMPs), and some have intriguing abilities to associate with the pericellular environment. It has been shown that TIMP-2 can bind to cell surface MT1-MMP (membrane-type 1 MMP) to act as a 'receptor' for proMMP-2 (progelatinase A), such that the latter can be activated efficiently in a localized fashion. We have examined the key structural features of TIMP-2 that determine this unique function, showing that Tyr36 and Glu192-Asp193 are vital for specific interactions with MT1-MMP and proMMP-2 respectively, and hence activation of proMMP-2. TIMP-3 is sequestered at the cell surface by association with the glycosaminoglycan chains of proteoglycans, especially heparan sulphate, and we have shown that it may play a role in the regulation of some ADAMs (a disintegrin and metalloproteinases), including tumour necrosis factor alpha-converting enzyme (TACE; ADAM17). We have established that key residues in TIMP-3 determine its interaction with TACE. Further studies of the features of TIMP-3 that determine specific binding to both ADAM and glycosaminoglycan are required in order to understand these unique properties.
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K. gm290@cam.ac.uk
Gillian
G
Murphy
Vera
V
Knäuper
Meng-Huee
MH
Lee
Augustin
A
Amour
Joanna R
JR
Worley
Mike
M
Hutton
Susan
S
Atkinson
Magdalene
M
Rapti
Richard
R
Williamson
D000595:Amino Acid Sequence; D004789:Enzyme Activation; D006868:Hydrolysis; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D019714:Tissue Inhibitor of Metalloproteinases / Q000737:chemistry / Q000502:physiology*
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases