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From Proteopedia

Matrix Metalloproteinase-1

Matrix Metalloproteinase-1 or MMP-1, is found in the extracellular matrix of cells throughout the body. It participates in a wide variety of physiological processes including wound healing, tissue repair, and remodeling (Nagase, Visse, & Murphy, 2006). Composed of a propeptide domain, a catalytic domain, a linker peptide, and a hemopexin domain, MMP-1 catalyzes the peptide bond hydrolysis of collagen (Nagase, et al., 2006). MMP-1 can be induced by growth factors, cytokines, and physical stress, among other things. Additionally, suppression can occur through glucocorticoids and retinoic acid (Nagase & Woessner, 1999).

Structure and Function

MMP-1 has a highly conserved structure consisting of four domains: a propeptide domain, a catalytic domain, a linker peptide, and a hemopexin domain containing a four bladed β-propeller. The catalytic domain contains a 5 stranded β-sheet and 3 α- helices, stabilized by one catalytic and one structural zinc ion and usually 3 calcium ions (Nagase & Woessner, 1999). The catalytic zinc is coordinated by three histidine residues and a water molecule, and is supported by the surrounding loop region containing a highly conserved “Met-turn” structure (Visse & Nagase, 2003). In its native, triple helical conformation, collagen is too wide to be accommodated by the narrow enzyme cleft, and the enzyme must unwind the collagen locally prior to peptide bond hydrolysis. Manka et al. (2012) identified several interactions between collagen and the MMP-1 catalytic domain, the majority of which are polar in nature:

• The Gln(P4’L) residue closest to the S1’ pocket forms a hydrogen bond with the backbone amide of Tyr221 at the entrance of the enzyme’s pocket as well as a hydrogen bond with the side chain of Asn161.
• The Arg(P5’L) side chain forms a hydrogen bond with the side chain of Tyr218 as well as a hydrogen bond with the carbonyl oxygen of Pro219.
• The enzyme’s hydrophobic S10’ exosite pocket, formed by Ile171, Met276, Phe301, Trp302, and the alkyl portion of Arg272, binds the side chain of Leu(P10’M). The pocket is surrounded by polar residues- Arg272, Glu274, Arg285, and Gln335- which form 5 hydrogen bonds with the collagen peptide.
• Hydrophobic interactions are formed with Val300 and Phe301.
• van der Waals contacts form between the M and T collagen chains and Phe289 and Tyr290.

When a substrate binds the catalytic site, the carbonyl group of the peptide bonds of His199, His203, and His209 coordinate the zinc- which acts as a Lewis acid- in the enzyme’s active site (Iyer, Visse, Nagase, & Acharya, 2006). This displaces a water molecule from the zinc. The water molecule then becomes a proton donor for the carboxyl group of Glu200; the water molecule attacks the carbonyl carbon of the peptide scissile bond (Iyer, Visse, Nagase, & Acharya, 2006). The S1’ pocket is then able to accommodate the substrate’s side chain which, after cleavage, becomes the new N-terminus (Visse & Nagase, 2003).

Regulation

MMP-1 is an inducible enzyme, and its effectors include growth factors, cytokines, and oncogenic cellular transformation. The MMP induced is dependent on certain signaling pathways. For example, the ceramide-dependent expression of MMP-1 in fibroblasts results from three MAP-kinase pathways (Nagase & Woessner, 1999). Additionally, MMP-1 is upregulated by exposure to Ultraviolet B radiation via production of reactive oxygen species through a stress-activated protein kinase.

Disease

MMP-1 has been implicated in several diseases, including Intervertebral Disc Disease, ulcers, arthritis, hepatitis C, and Chronic Obstructive Pulmonary Disorder (Russell, Culpitt, DeMatos, Donnelly, Smith, Wiggins, & Barnes, 2002; Roberts, Caterson, Menage, Evans, Jaffray, & Eisenstein, 2000). These disorders involve the decrease in Tissue Inhibitor of Matrix Metalloproteinase-1, resulting in an upregulation of MMP-1 and thus an increase in the metabolism of the extracellular matrix eventually leading to symptomatic presentation of illness (Russell, Culpitt, DeMatos, Donnelly, Smith, Wiggins, & Barnes, 2002). For example, in Intervertebral Disc Disease, the ongoing metabolism of the extracellular matrix in the intervertebral disc leads to dehydration of the disc, decreased height of the disc, and decreased shock absorbing ability causing pain at the affected spinal level(s).

References

Iyer, S., Visse, R., Nagase, H., & Acharya, K. R. (2006). Crystal Structure of an Active Form of Human MMP-1. Journal of Molecular Biology, 362(1), 78–88. doi:10.1016/j.jmb.2006.06.079

Manka, S. W., Carafoli, F., Visse, R., Bihan, D., Raynal, N., Farndale, R. W., ... & Nagase, H. (2012). Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1. Proceedings of the National Academy of Sciences, 109(31), 12461-12466.

Nagase, H., & Woessner, J. F. (1999). Matrix metalloproteinases. Journal of Biological Chemistry, 274(31), 21491-21494.

Nagase, H., Visse, R., & Murphy, G. (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular research, 69(3), 562-573.

Roberts, S., Caterson, B., Menage, J., Evans, E. H., Jaffray, D. C., & Eisenstein, S. M. (2000). Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine, 25(23), 3005-3013.

Russell, R. E., Culpitt, S. V., DeMatos, C., Donnelly, L., Smith, M., Wiggins, J., & Barnes, P. J. (2002). Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. American journal of respiratory cell and molecular biology, 26(5), 602-609.

Visse, R., & Nagase, H. (2003). Matrix metalloproteinases and tissue inhibitors of metalloproteinases structure, function, and biochemistry. Circulation research, 92(8), 827-839.