Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease
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Collagen is a macromolecule that has versatile roles in physiology, ranging from structural support to mediating cell signaling. Formation of mature collagen fibrils out of procollagen α-chains requires a variety of enzymes and chaperones in a complex process spanning both intracellular and extracellular post-translational modifications. These processes include modifications of amino acids, folding of procollagen α-chains into a triple-helical configuration and subsequent stabilization, facilitation of transportation out of the cell, cleavage of propeptides, aggregation, cross-link formation, and finally the formation of mature fibrils. Disruption of any of the proteins involved in these biosynthesis steps potentially result in a variety of connective tissue diseases because of a destabilized extracellular matrix. In this review, we give a revised overview of the enzymes and chaperones currently known to be relevant to the conversion of lysine and proline into hydroxyproline and hydroxylysine, respectively, and the O-glycosylation of hydroxylysine and give insights into the consequences when these steps are disrupted.
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P4HA2 and P4HA3 encode two of the three isoforms of the α-subunit of collagen prolyl-4-hydroxylase, a tetrameric enzyme resident in the ER lumen that hydroxylates prolines on the procollagen peptide and serves as a chaperone for procollagen.
“P4HA2 and P4HA3 encode two of the three isoforms of the α-subunit of collagen prolyl-4-hydroxylase, a tetrameric enzyme resident in the ER lumen that hydroxylates prolines on the procollagen peptide and serves as a chaperone for procollagen [39].”
FKBP14 encodes FKBP22, a peptidyl-prolyl cis-trans isomerase localized in the ER lumen that interacts with different types of COLLs and catalyzes cis-trans-isomerization of peptide bonds, promoting COLLIII folding.
“FKBP14 encodes FKBP22, a peptidyl-prolyl cis-trans isomerase localized in the ER lumen [41] that interacts with different types of COLLs, i.e., COLLIII, COLLVI, and COLLX, and during COLLs triple helix formation catalyzes cis–trans-isomerization of peptide bonds, promoting in particular the COLLIII folding [39,42].”
Hydroxylation of COLLs prolyl residues is essential for proper assembly and thermal stabilization of COLLs triple helices through intramolecular hydrogen bonding.
“Hydroxylation of COLLs prolyl residues is essential for proper assembly and thermal stabilization of COLLs triple helices through intramolecular hydrogen bonding [40], since under-hydroxylation results in abnormal assembly, and reduced thermal stability of newly synthesized procollagen chains [39].”
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References 177 · Cited by 175
- Authors
- Gjaltema, R. A. F., & Bank, R. A.
- Affiliations
- University Medical Center Groningen (NL)
- Corresponding author
- Bank, Ruud A.
- Venue
- Critical Reviews in Biochemistry and Molecular Biology
- Publisher
- Informa UK Limited
- Published
- 2016-12-23
- Volume
- 52
- Issue
- 1
- Pages
- 74-95
- ISSN
- 0045-6411 (ISSN-L)
- 1040-9238
- 1549-7798
- OpenAlex
- W2561313757
- Cited by
- 175
- References
- 177
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 29 · 2020: 19 · 2019: 27 · 2018: 15 · 2017: 7
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Critical Reviews in Biochemistry and Molecular Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Dutch government (FES0908)
- the Dutch government (FES0908)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Collagen: Extraction and Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Keywords
- collagen hydroxylation, prolyl hydroxylase, lysyl hydroxylase, hydroxyproline, hydroxylysine, O-glycosylation, collagen fibril formation, procollagen processing, collagen synthesis, connective tissue diseases, extracellular matrix, molecular chaperones
- MeSH terms
- Animals, Arthrogryposis, Connective Tissue Diseases, Ehlers-Danlos Syndrome, Glycosylation, Humans, Hydroxylation, Hydroxylysine, Hydroxyproline, Lysine, Osteogenesis Imperfecta, Proline, Protein Folding, Fibrillar Collagens
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