Computational insights into the substrate recognition mechanism of cartilage extracellular matrix degradation
Journal
Computational and Structural Biotechnology Journal
Journal Volume
19
Pages
5535-5545
Date Issued
2021
Author(s)
Abstract
Articular cartilage is connective tissue that forms a slippery load-bearing joint surface between bones. With outstanding mechanical properties, it plays an essential role in cushioning impact and protecting the ends of bones. Abnormal mechanical stimulation, such as repetitive overloading or chondral injury, induces excessive cartilage extracellular matrix (ECM) degradation, leading to osteoarthritis and other joint disorders. A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is an aggrecanase that dominates the catalysis of aggrecan, the major proteoglycan in the cartilage ECM. Intriguingly, unlike its critical cleavage site Glu373–374Ala, another potential cleavage site, Glu419-420Ala, composed of the same amino acids in the aggrecan interglobular domain, is not a major cleavage site. It remains unclear how ADAMTS-5 distinguishes between them and hydrolyzes the correct scissile bonds. This research introduces a bottom-up in silico approach to reveal the molecular mechanism by which ADAMTS-5 recognizes the cleavage site on aggrecan. It is hypothesized that the sequence in the vicinity assists ADAMTS-5 in positioning the cleavage site. Specific residues were found to serve as binding sites, helping aggrecan bind more stably and fit into the enzyme better. The findings provide insight into the substrate binding and recognition mechanism for cartilage ECM degradation from a brand new atomic-scale perspective, laying the foundation for prophylaxis and treatment of related joint diseases. ? 2021 The Authors
Subjects
ADAMTS-5
Aggrecan
Degradation
Extracellular matrix
Molecular dynamics
Osteoarthritis
Binding sites
Bioinformatics
Cartilage
Collagen
Computational chemistry
Joints (anatomy)
A disintegrin and metalloproteinase with thrombospondin motif-5
Cartilage extracellular matrixes
Cleavage sites
Disintegrins
Extracellular matrices
Extracellular matrix degradation
Metalloproteinases
Substrate recognition
Thrombospondin motifs
Glycoproteins
aggrecan
aggrecanase 2
amino acid
proteoglycan
arthropathy
Article
binding affinity
cartilage degeneration
catalysis
computer model
enzyme active site
enzyme structure
extracellular matrix
human
hydrogen bond
hydrolysis
mechanical stimulation
molecular mechanics
osteoarthritis
SDGs
Type
journal article