Insights into the degradation of human elastin by matrilysin-1

TY - JOUR

T1 - Insights into the degradation of human elastin by matrilysin-1

AU - Heinz, Andrea

AU - Taddese, Samuel

AU - Sippl, Wolfgang

AU - Neubert, Reinhard H H

AU - Schmelzer, Christian E H

N1 - Copyright © 2010 Elsevier Masson SAS. All rights reserved.

PY - 2011/2

Y1 - 2011/2

N2 - Human matrilysin-1 (MMP-7) is one of the most potent elastases besides macrophage elastase in the family of matrix metalloproteinases (MMPs). It has been reported to provide macrophages with the highest elastinolytic capacity and plays key roles in diseases such as emphysema and cancer. Describing the enzymatic turnover of matrix components helps to understand the molecular basis of disease processes. Hence, in this work, the cleavage behavior of MMP-7 with respect to its natural substrate human elastin was investigated using mass spectrometric (MS) techniques and molecular modeling. Elastin peptides in the range of 500-8000 Da released through the action of MMP-7 were analyzed and domains susceptible to proteolytic attack by MMP-7 were identified. MMP-7 was found to mainly cleave in N- and C-terminal regions of elastin's precursor, which involves linkages in domains encoded by exons 2, 3, 5-7, 26, and 30-33. In contrast, only few cleavages were found in the central part of the precursor and no cleavages in regions in elastin that are involved in cross-linking. MMP-7 shows a strong preference for Leu in P(1)' and also accepts Val, Gly, and Pro at this position, whereas Ala is not preferred at P(1)'. Analysis by molecular modeling revealed that not only the size of the amino acid residue in P(1)' but also the orientation of the neighboring P(1) residue and, thus, the orientation of the peptide bond that is cleaved influences the cleavage preference of MMP-7. Overall, this study provides an important insight into the degradation of human elastin by MMP-7 and may aid in the development of approaches to treat elastin-degrading diseases.

AB - Human matrilysin-1 (MMP-7) is one of the most potent elastases besides macrophage elastase in the family of matrix metalloproteinases (MMPs). It has been reported to provide macrophages with the highest elastinolytic capacity and plays key roles in diseases such as emphysema and cancer. Describing the enzymatic turnover of matrix components helps to understand the molecular basis of disease processes. Hence, in this work, the cleavage behavior of MMP-7 with respect to its natural substrate human elastin was investigated using mass spectrometric (MS) techniques and molecular modeling. Elastin peptides in the range of 500-8000 Da released through the action of MMP-7 were analyzed and domains susceptible to proteolytic attack by MMP-7 were identified. MMP-7 was found to mainly cleave in N- and C-terminal regions of elastin's precursor, which involves linkages in domains encoded by exons 2, 3, 5-7, 26, and 30-33. In contrast, only few cleavages were found in the central part of the precursor and no cleavages in regions in elastin that are involved in cross-linking. MMP-7 shows a strong preference for Leu in P(1)' and also accepts Val, Gly, and Pro at this position, whereas Ala is not preferred at P(1)'. Analysis by molecular modeling revealed that not only the size of the amino acid residue in P(1)' but also the orientation of the neighboring P(1) residue and, thus, the orientation of the peptide bond that is cleaved influences the cleavage preference of MMP-7. Overall, this study provides an important insight into the degradation of human elastin by MMP-7 and may aid in the development of approaches to treat elastin-degrading diseases.

KW - Amino Acid Sequence

KW - Binding Sites

KW - Chromatography, High Pressure Liquid

KW - Elastin

KW - Humans

KW - Matrix Metalloproteinase 7

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Nanotechnology

KW - Protein Binding

KW - Protein Conformation

KW - Protein Isoforms

KW - Protein Processing, Post-Translational

KW - Substrate Specificity

KW - Tandem Mass Spectrometry

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.biochi.2010.09.011

DO - 10.1016/j.biochi.2010.09.011

M3 - Journal article

C2 - 20884320

SN - 0300-9084

VL - 93

SP - 187

EP - 194

JO - Biochimie

JF - Biochimie

IS - 2

ER -