TY - JOUR
T1 - MMP-12 catalytic domain recognizes and cleaves at multiple sites in human skin collagen type I and type III
AU - Taddese, Samuel
AU - Jung, Michael C
AU - Ihling, Christian
AU - Heinz, Andrea
AU - Neubert, Reinhard H H
AU - Schmelzer, Christian E H
N1 - Copyright 2009 Elsevier B.V. All rights reserved.
PY - 2010/4
Y1 - 2010/4
N2 - Collagens of either soft connective or mineralized tissues are subject to continuous remodeling and turnover. Undesired cleavage can be the result of an imbalance between proteases and their inhibitors. Owing to their superhelical structure, collagens are resistant to many proteases and matrix metalloproteinases (MMPs) are required to initiate further degradation by other enzymes. Several MMPs are known to degrade collagens, but the action of MMP-12 has not yet been studied in detail. In this work, the potential of MMP-12 in recognizing sites in human skin collagen types I and III has been investigated. The catalytic domain of MMP-12 binds to the triple helix and cleaves the typical sites -Gly775-Leu776- in α-2 type I collagen and -Gly775-Ile776- in α-1 type I and type III collagens and at multiple other sites in both collagen types. Moreover, it was observed that the region around these typical sites contains comparatively less prolines, of which some have been proven to be only partially hydroxylated. This is of relevance since partial hydroxylation in the vicinity of a potential scissile bond may have a local effect on the conformational thermodynamics with probable consequences on the collagenolysis process. Taken together, the results of the present work confirm that the catalytic domain of MMP-12 alone binds and degrades collagens I and III.
AB - Collagens of either soft connective or mineralized tissues are subject to continuous remodeling and turnover. Undesired cleavage can be the result of an imbalance between proteases and their inhibitors. Owing to their superhelical structure, collagens are resistant to many proteases and matrix metalloproteinases (MMPs) are required to initiate further degradation by other enzymes. Several MMPs are known to degrade collagens, but the action of MMP-12 has not yet been studied in detail. In this work, the potential of MMP-12 in recognizing sites in human skin collagen types I and III has been investigated. The catalytic domain of MMP-12 binds to the triple helix and cleaves the typical sites -Gly775-Leu776- in α-2 type I collagen and -Gly775-Ile776- in α-1 type I and type III collagens and at multiple other sites in both collagen types. Moreover, it was observed that the region around these typical sites contains comparatively less prolines, of which some have been proven to be only partially hydroxylated. This is of relevance since partial hydroxylation in the vicinity of a potential scissile bond may have a local effect on the conformational thermodynamics with probable consequences on the collagenolysis process. Taken together, the results of the present work confirm that the catalytic domain of MMP-12 alone binds and degrades collagens I and III.
KW - Amino Acid Sequence
KW - Binding Sites
KW - Catalytic Domain
KW - Chromatography, High Pressure Liquid
KW - Collagen
KW - Collagen Type I
KW - Collagen Type III
KW - Humans
KW - Hydroxylation
KW - In Vitro Techniques
KW - Matrix Metalloproteinase 12
KW - Molecular Sequence Data
KW - Peptide Fragments
KW - Protein Conformation
KW - Protein Structure, Tertiary
KW - Recombinant Proteins
KW - Skin
KW - Spectrometry, Mass, Electrospray Ionization
KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
KW - Tandem Mass Spectrometry
KW - Thermodynamics
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.bbapap.2009.11.014
DO - 10.1016/j.bbapap.2009.11.014
M3 - Journal article
C2 - 19932771
SN - 0006-3002
VL - 1804
SP - 731
EP - 739
JO - B B A - Reviews on Cancer
JF - B B A - Reviews on Cancer
IS - 4
ER -