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Tissue inhibitor of metalloproteinases-4. The road less traveled.

Melendez-Zajgla J, Del Pozo L, Ceballos G, Maldonado V - Mol. Cancer (2008)

Bottom Line: Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs).Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions.This restricted expression suggests specific and different physiological functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto Nacional de Medicina Genomica, Mexico. jorgezajgla@gmail.com

ABSTRACT
Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer.

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Cartoon representation of the crystallography structure of the human TIMP-2 in uncomplexed state (A) and the bovine TIMP-2 complexed with the catalytic domain on the metalloproteinase 13 (cdMMP-13) (B). The regions of TIMP-2 folded as helices and β-strands are colored in red and yellow, respectively. The six conserved disulfide bridges characterizing the TIMP structure are shown in blue in figure A. In B, the cdMMP-13 is colored in blue and the catalytic Zn is colored in magenta and shown in space-filled format. The residues Cys1, Ser2 and Cys3 that form the core of the molecular edge of the inhibitor that occupies the active-site cleft of the MMP, and the Cys72 and Cys101 are shown in stick format and colored yellow. The figure was prepared using PyMOL® and the coordinates of PDB 1BR9 (Fig. 2A) and PDB 2E2D (Fig. 2B).
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Figure 2: Cartoon representation of the crystallography structure of the human TIMP-2 in uncomplexed state (A) and the bovine TIMP-2 complexed with the catalytic domain on the metalloproteinase 13 (cdMMP-13) (B). The regions of TIMP-2 folded as helices and β-strands are colored in red and yellow, respectively. The six conserved disulfide bridges characterizing the TIMP structure are shown in blue in figure A. In B, the cdMMP-13 is colored in blue and the catalytic Zn is colored in magenta and shown in space-filled format. The residues Cys1, Ser2 and Cys3 that form the core of the molecular edge of the inhibitor that occupies the active-site cleft of the MMP, and the Cys72 and Cys101 are shown in stick format and colored yellow. The figure was prepared using PyMOL® and the coordinates of PDB 1BR9 (Fig. 2A) and PDB 2E2D (Fig. 2B).

Mentions: Human TIMP-4 is a non-glycosylated, 195 amino acids long polypeptide, the largest of the currently identified human inhibitors of matrix metalloproteinases (MMP) (Fig 1). TIMP-4 and TIMP-2 are 51% identical at the amino acid level, with TIMP-4 only one residue larger than TIMP-2. Contrastingly, TIMP-4 is eleven and seven residues larger than TIMP-1 and TIMP-3 and shows 37% and 51% identity to these proteins, respectively [6-9] (Table 1). Distinctive within the TIMP family, TIMP-4 has twelve Cys residues that form six conserved disulfide bridges [8,10]. The three-dimensional (3D) structure of TIMP-4 has not yet been determined, but due to the relative high sequence identity it shares with the other TIMPs, in particular to TIMP-2, a high structural similarity to those proteins could be expected [7]. The TIMPs fold into two very distinct domains, a larger N-terminal domain that carries the MMP inhibitory activity and a smaller C-terminal domain that mediates other non-inhibitory interactions, notably with some pro-MMP forms (Fig 2A) [8,9,11-13]. The N-terminal domain encompasses nearly two-thirds of the polypeptide chain and is reminiscent of the oligonucleotide/oligosaccharide-binding (OB) fold [14-19]. This motif was first described in proteins binding oligonucleotides or oligossacharides [20] and is present in twelve protein superfamilies within the SCOPE (Structural Classification of Proteins, ) data base, including the staphylococcal nucleases, bacterial enterotoxins, heme chaperone CcmE, N-terminal domain of the tail-associated lysozyme gp5 of bacteriophage T4, nucleic acid-binding proteins and inorganic pyrophosphatases, among others [21,22]. The core of the TIMP OB region is formed by a five-stranded anti-parallel β pleated sheet rolled into a β-barrel, stabilized by three disulfide bonds. The strands forming the barrel are connected by loops, which in some cases differ in length from one TIMP to another. Three segments folded in α-helices (α-helix 1 to 3) are associated with the β-barrel core (Fig 2A) [8,12,14-18,23-26]. The N-terminal domain can be expressed and folded independently and, as it was pointed out above, is necessary and sufficient for MMP inhibition [15,27-29].


Tissue inhibitor of metalloproteinases-4. The road less traveled.

Melendez-Zajgla J, Del Pozo L, Ceballos G, Maldonado V - Mol. Cancer (2008)

Cartoon representation of the crystallography structure of the human TIMP-2 in uncomplexed state (A) and the bovine TIMP-2 complexed with the catalytic domain on the metalloproteinase 13 (cdMMP-13) (B). The regions of TIMP-2 folded as helices and β-strands are colored in red and yellow, respectively. The six conserved disulfide bridges characterizing the TIMP structure are shown in blue in figure A. In B, the cdMMP-13 is colored in blue and the catalytic Zn is colored in magenta and shown in space-filled format. The residues Cys1, Ser2 and Cys3 that form the core of the molecular edge of the inhibitor that occupies the active-site cleft of the MMP, and the Cys72 and Cys101 are shown in stick format and colored yellow. The figure was prepared using PyMOL® and the coordinates of PDB 1BR9 (Fig. 2A) and PDB 2E2D (Fig. 2B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2599898&req=5

Figure 2: Cartoon representation of the crystallography structure of the human TIMP-2 in uncomplexed state (A) and the bovine TIMP-2 complexed with the catalytic domain on the metalloproteinase 13 (cdMMP-13) (B). The regions of TIMP-2 folded as helices and β-strands are colored in red and yellow, respectively. The six conserved disulfide bridges characterizing the TIMP structure are shown in blue in figure A. In B, the cdMMP-13 is colored in blue and the catalytic Zn is colored in magenta and shown in space-filled format. The residues Cys1, Ser2 and Cys3 that form the core of the molecular edge of the inhibitor that occupies the active-site cleft of the MMP, and the Cys72 and Cys101 are shown in stick format and colored yellow. The figure was prepared using PyMOL® and the coordinates of PDB 1BR9 (Fig. 2A) and PDB 2E2D (Fig. 2B).
Mentions: Human TIMP-4 is a non-glycosylated, 195 amino acids long polypeptide, the largest of the currently identified human inhibitors of matrix metalloproteinases (MMP) (Fig 1). TIMP-4 and TIMP-2 are 51% identical at the amino acid level, with TIMP-4 only one residue larger than TIMP-2. Contrastingly, TIMP-4 is eleven and seven residues larger than TIMP-1 and TIMP-3 and shows 37% and 51% identity to these proteins, respectively [6-9] (Table 1). Distinctive within the TIMP family, TIMP-4 has twelve Cys residues that form six conserved disulfide bridges [8,10]. The three-dimensional (3D) structure of TIMP-4 has not yet been determined, but due to the relative high sequence identity it shares with the other TIMPs, in particular to TIMP-2, a high structural similarity to those proteins could be expected [7]. The TIMPs fold into two very distinct domains, a larger N-terminal domain that carries the MMP inhibitory activity and a smaller C-terminal domain that mediates other non-inhibitory interactions, notably with some pro-MMP forms (Fig 2A) [8,9,11-13]. The N-terminal domain encompasses nearly two-thirds of the polypeptide chain and is reminiscent of the oligonucleotide/oligosaccharide-binding (OB) fold [14-19]. This motif was first described in proteins binding oligonucleotides or oligossacharides [20] and is present in twelve protein superfamilies within the SCOPE (Structural Classification of Proteins, ) data base, including the staphylococcal nucleases, bacterial enterotoxins, heme chaperone CcmE, N-terminal domain of the tail-associated lysozyme gp5 of bacteriophage T4, nucleic acid-binding proteins and inorganic pyrophosphatases, among others [21,22]. The core of the TIMP OB region is formed by a five-stranded anti-parallel β pleated sheet rolled into a β-barrel, stabilized by three disulfide bonds. The strands forming the barrel are connected by loops, which in some cases differ in length from one TIMP to another. Three segments folded in α-helices (α-helix 1 to 3) are associated with the β-barrel core (Fig 2A) [8,12,14-18,23-26]. The N-terminal domain can be expressed and folded independently and, as it was pointed out above, is necessary and sufficient for MMP inhibition [15,27-29].

Bottom Line: Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs).Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions.This restricted expression suggests specific and different physiological functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto Nacional de Medicina Genomica, Mexico. jorgezajgla@gmail.com

ABSTRACT
Tissue inhibitors of metalloproteinases (TIMPs) regulate diverse processes, including extracellular matrix (ECM) remodeling, and growth factors and their receptors' activities through the inhibition of matrix metalloproteinases (MMPs). Recent evidence has shown that this family of four members (TIMP-1 to TIMP-4) can also control other important processes, such as proliferation and apoptosis, by a mechanism independent of their MMP inhibitory actions. Of these inhibitors, the most recently identified and least studied is TIMP-4. Initially cloned in human and, later, in mouse, TIMP-4 expression is restricted to heart, kidney, pancreas, colon, testes, brain and adipose tissue. This restricted expression suggests specific and different physiological functions. The present review summarizes the information available for this protein and also provides a putative structural model in order to propose potential relevant directions toward solving its function and role in diseases such as cancer.

Show MeSH
Related in: MedlinePlus