title: Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen.
abstract: Covalent intermolecular cross-linking provides collagen fibrils with stability. The cross-linking chemistry is tissue-specific and determined primarily by the state of lysine hydroxylation at specific sites. A recent study on cyclophilin B (CypB) null mice, a model of recessive osteogenesis imperfecta, demonstrated that lysine hydroxylation at the helical cross-linking site of bone type I collagen was diminished in these animals (Cabral, W. A., Perdivara, I., Weis, M., Terajima, M., Blissett, A. R., Chang, W., Perosky, J. E., Makareeva, E. N., Mertz, E. L., Leikin, S., Tomer, K. B., Kozloff, K. M., Eyre, D. R., Yamauchi, M., and Marini, J. C. (2014) PLoS Genet 10, e1004465). However, the extent of decrease appears to be tissue- and molecular site-specific, the mechanism of which is unknown. Here we report that although CypB deficiency resulted in lower lysine hydroxylation in the helical cross-linking sites, it was increased in the telopeptide cross-linking sites in tendon type I collagen. This resulted in a decrease in the lysine aldehyde-derived cross-links but generation of hydroxylysine aldehyde-derived cross-links. The latter were absent from the wild type and heterozygous mice. Glycosylation of hydroxylysine residues was moderately increased in the CypB null tendon. We found that CypB interacted with all lysyl hydroxylase isoforms (isoforms 1-3) and a putative lysyl hydroxylase-2 chaperone, 65-kDa FK506-binding protein. Tendon collagen in CypB null mice showed severe size and organizational abnormalities. The data indicate that CypB modulates collagen cross-linking by differentially affecting lysine hydroxylation in a site-specific manner, possibly via its interaction with lysyl hydroxylases and associated molecules. This study underscores the critical importance of collagen post-translational modifications in connective tissue formation.
authors.affiliation: From the North Carolina Oral Health Institute, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Terajima
authors.affiliation: the Nippi Research Institute of Biomatrix, Ibaraki 302-0017, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Taga
authors.affiliation: the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: the Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.affiliation: the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Guo
authors.initials: G
authors.lastname: Hou-Fu
authors.affiliation: the Departments of Operative Dentistry, Chulalongkorn University, Bangkok 10330, Thailand, and.
authors.forename: Sirivimol
authors.initials: S
authors.lastname: Srisawasdi
authors.affiliation: the Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Nagasawa
authors.affiliation: From the North Carolina Oral Health Institute, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sumida
authors.affiliation: the Nippi Research Institute of Biomatrix, Ibaraki 302-0017, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Hattori
authors.affiliation: the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.affiliation: the Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: From the North Carolina Oral Health Institute, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina 27599, mitsuo_yamauchi@unc.edu.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamauchi
mesh_terms: D000818:Animals; D003094:Collagen / Q000737:chemistry; D024042:Collagen Type I / Q000737:chemistry*; D021983:Cyclophilins / Q000378:metabolism; D006900:Hydroxylation; D008239:Lysine / Q000737:chemistry*; D013710:Tendons / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D003094:Collagen; D021983:Cyclophilins; D008239:Lysine
keywords: collagen; cyclophilin; glycosylation; hydroxylysine (Hyl); molecular chaperone; post-translational modification (PTM); tendon