ArticleProceedings of the National Academy of Sciences of the United States of America2014
Structural basis of collagen fiber degradation by cathepsin K.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 143 citations in OpenAlex.
- Exploration of tropocollagen unwinding by cathepsin K dimer with chondroitin 4-sulphate through microsecond timescale molecular dynamics.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Heparan sulfate promotes autoactivation of procathepsin K by destabilizing the propeptide-catalytic domain interaction.The Biochemical journal · 2026Article
- Comparison of Protein-Glycosaminoglycan Interactions in ff14sb/GLYCAM06j-1 and CHARMM36m Force Fields.Journal of chemical information and modeling · 2026Article
- Bone adhesive with temporally-synchronized degradation for enhanced osteointegration.Bone research · 2026Article
- The protease cathepsin K can debulk the cancer glycocalyx.The Journal of biological chemistry · 2026Article
- Integration of cAMP and TRPV4 Signaling to Optimize Collagen Remodeling for Management of Fibrosis.Cells · 2025Review
- In tendons, differing physiological requirements lead to distinct patterns of MMP-1 degradation.Scientific reports · 2025Article
- Sustained release of cathepsin D/cathepsin K from injectable hydrogel microspheres in anti-photoaging.Materials today. Bio · 2025Article
- Cathepsins: Emerging targets in the tumor ecosystem to overcome cancers.Seminars in cancer biology · 2025Review
- Small-molecule Cathepsin K inhibitors: a medicinal chemistry perspective.Future medicinal chemistry · 2025Review
- Proteins and DNA Sequences Interacting with Tanshinones and Tanshinone Derivatives.International journal of molecular sciences · 2025Review
- PKM2 orchestrates tumor progression via metabolic reprogramming and MDSCs-mediated immune suppression in the tumor microenvironment.Frontiers in immunology · 2025Review
- Application of collagen in bone regeneration.Journal of orthopaedic translation · 2025Review
- The multifaceted roles of cathepsins in immune and inflammatory responses: implications for cancer therapy, autoimmune diseases, and infectious diseases.Biomarker research · 2024Review
- Understanding the Causes of Keel Bone Damage and Its Effects on the Welfare of Laying Hens.Animals : an open access journal from MDPI · 2024Review
- Development and Application of Reversible and Irreversible Covalent Probes for Human and Mouse Cathepsin-K Activity Detection, Revealing Nuclear Activity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Heparan sulfate selectively inhibits the collagenase activity of cathepsin K.Matrix biology : journal of the International Society for Matrix Biology · 2024Article
- Real-time analysis of osteoclast resorption and fusion dynamics in response to bone resorption inhibitors.Scientific reports · 2024Article
- HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy.Journal of translational medicine · 2024Article
- An Unusual Two-Domain Thyropin from Tick Saliva: NMR Solution Structure and Highly Selective Inhibition of Cysteine Cathepsins Modulated by Glycosaminoglycans.International journal of molecular sciences · 2024Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Cathepsin K is the major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation. Despite its key role in bone remodeling and for being a highly sought-after drug target for the treatment of osteoporosis, the mechanism of collagen fiber degradation by cathepsin K remained elusive. Here, we report the structure of a collagenolytically active cathepsin K protein dimer. Cathepsin K is organized into elongated C-shaped protease dimers that reveal a putative collagen-binding interface aided by glycosaminoglycans. Molecular modeling of collagen binding to the dimer indicates the participation of nonactive site amino acid residues, Q21 and Q92, in collagen unfolding. Mutations at these sites as well as perturbation of the dimer protein-protein interface completely inhibit cathepsin-K-mediated fiber degradation without affecting the hydrolysis of gelatin or synthetic peptide. Using scanning electron microscopy, we demonstrate the specific binding of cathepsin K at the edge of the fibrillar gap region of collagen fibers, which suggest initial cleavage events at the N- and C-terminal ends of tropocollagen molecules. Edman degradation analysis of collagen fiber degradation products revealed those initial cleavage sites. We propose that one cathepsin K molecule binds to collagen-bound glycosaminoglycans at the gap region and recruits a second protease molecule that provides an unfolding and cleavage mechanism for triple helical collagen. Removal of collagen-associated glycosaminoglycans prevents cathepsin K binding and subsequently fiber hydrolysis. Cathepsin K dimer and glycosaminoglycan binding sites represent novel targeting sites for the development of nonactive site-directed second-generation inhibitors of this important drug target.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.