F
IPR001820

Protease inhibitor I35 (TIMP)

InterPro entry
Short nameTIMP
Overlapping
homologous
superfamilies
 

Description

Tissue inhibitors of metalloproteinases (TIMPs,
[1, 2, 3, 8, 7]
) and their target matrix metalloproteinases (MMPs, MEROPS peptidase family M10A) are important in connective tissue re-modelling in diseases of the cardiovascular system and in the physiological degradation of connective tissue, as well as in pathological states such as tumour invasion and arthritis. TIMPs belong to MEROPS proteinase inhibitor family I35, clan IT.

TIMPs complex with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them. Members of this family are common in extracellular regions of vertebrate species
[4]
. TIMPs are proteins of about 200 amino acid residues, 12 of which are cysteines involved in disulphide bonds
[5]
. The basic structure of such a type of inhibitor is shown in the following schematic representation:

          +-----------------------------+         +--------------+
          |                             |         |              |
        CxCxCxxxxxxxxxxxxxxxxxCxxxxxxxxxCxxxxxxxCxCxCxCxCxxxxxCxxCxxx
        |   |                 |                 |   | | |     |
        |   +-----------------|-----------------+   +-+ +-----+
        +---------------------+
'C': conserved cysteine involved in a disulphide bond.

The crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterised by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for non-inhibitory MMP/TIMP complex formation is achieved
[6]
.

References

1.Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. Stetler-Stevenson WG, Krutzsch HC, Liotta LA. J. Biol. Chem. 264, 17374-8, (1989). View articlePMID: 2793861

2.Matrix metalloproteinases and their inhibitors in connective tissue remodeling. Woessner JF Jr. FASEB J. 5, 2145-54, (1991). View articlePMID: 1850705

3.A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. Pavloff N, Staskus PW, Kishnani NS, Hawkes SP. J. Biol. Chem. 267, 17321-6, (1992). View articlePMID: 1512267

4.Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family. Williamson RA, Martorell G, Carr MD, Murphy G, Docherty AJ, Freedman RB, Feeney J. Biochemistry 33, 11745-59, (1994). View articlePMID: 7918391

5.Disulphide bond assignment in human tissue inhibitor of metalloproteinases (TIMP). Williamson RA, Marston FA, Angal S, Koklitis P, Panico M, Morris HR, Carne AF, Smith BJ, Harris TJ, Freedman RB. Biochem. J. 268, 267-74, (1990). View articlePMID: 2163605

6.Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Morgunova E, Tuuttila A, Bergmann U, Tryggvason K. Proc. Natl. Acad. Sci. U.S.A. 99, 7414-9, (2002). View articlePMID: 12032297

7.Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation. Toricelli M, Melo FH, Peres GB, Silva DC, Jasiulionis MG. Mol. Cancer 12, 22, (2013). PMID: 23522389

8.Matrix metalloproteinase-10 (MMP-10) interaction with tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2: binding studies and crystal structure. Batra J, Robinson J, Soares AS, Fields AP, Radisky DC, Radisky ES. J. Biol. Chem. 287, 15935-46, (2012). View articlePMID: 22427646

GO terms

biological process

  • None

cellular component

  • None

Cross References

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.