title: Insights into the degradation of human elastin by matrilysin-1.
abstract: 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.
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinz
authors.forename: Samuel
authors.initials: S
authors.lastname: Taddese
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Reinhard H H
authors.initials: RH
authors.lastname: Neubert
authors.forename: Christian E H
authors.initials: CE
authors.lastname: Schmelzer
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004549:Elastin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D036103:Nanotechnology; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D020033:Protein Isoforms; D004549:Elastin; D020783:Matrix Metalloproteinase 7