Mutation in Cyclophilin B That Causes Hyperelastosis Cutis in American Quarter Horse Does Not Affect Peptidylprolyl cis-trans Isomerase Activity but Shows Altered Cyclophilin B-Protein Interactions and Affects Collagen Folding

Ishikawa, Yoshihiro; Vranka, Janice A.; Boudko, Sergei P.; Pokidysheva, Elena; Mizuno, Kazunori; Zientek, Keith; Keene, Douglas R.; Rashmir‐Raven, Ann M.; Nagata, Kazuhiro; Winand, Nena J.; Bächinger, Hans Peter

doi:10.1074/jbc.m111.333336

Cited by 80 publications

(93 citation statements)

References 56 publications

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“…First, there was severe degeneration of tendon collagen matrices in KO, and the fibrils were markedly small, disorganized, and non-uniform. The fibrillar phenotype is similar to that seen in horse tendon with hyperelastosis cutis (28). Second, the effect on Lys hydroxylation in KO tendon collagen was distinct from both bone and skin collagen.…”

Section: Discussionsupporting

confidence: 58%

“…By analyzing skin and tendon type I collagen in American quarter horses with hyperelastosis cutis caused by a CypB missense mutation, Ishikawa et al was the first to report that CypB directly interacts with LH1 and may facilitate its function (28). An interesting finding in their report is that the extent of suppression in Lys hydroxylation of collagen was significantly different between the two tissues examined.…”

Section: Discussionmentioning

confidence: 99%

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Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

Terajima

Taga

Chen

et al. 2016

Journal of Biological Chemistry

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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.Collagens comprise a large family of structurally related extracellular matrix proteins (1). Among all of the genetic types of collagen identified, fibrillar type I collagen is the most abundant, providing tissues and organs with form and stability. It is a heterotrimeric molecule composed of two ␣1 chains and one ␣2 chain forming a long uninterrupted triple helix with short non-helical domains (telopeptide) at both N and C termini. One of the functionally important characteristics of collagen is its unique, sequential post-translational modifications of Lys residues. The modifications include hydroxylation and monoand diglycosylation of hydroxylysine (Hyl), 3 and oxidative deamination of Lys and Hyl in the N-and C-telopeptides followed by extensive covalent intermolecular cross-linking (2). It is now clear that defective Lys modifications of collagen cause and/or are associated with a broad range of connective tissue disorders, including Ehlers-Danlos syndrome type VIA (3), bronchopulmonary dysplasia (4), Kuskokwim syndrome (5), Bruck syndrome (6, 7), fibrosis (8), disuse osteoporosis (9), and cancer progression (10, 11). Our recent finding showed that a switch of collage...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

Terajima

Taga

Chen

et al. 2016

Journal of Biological Chemistry

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“…Both CypB and FKBP65 are involved in type I procollagen biosynthesis (7,(12)(13). Mutations in either PPIB (coding for CypB) or FKBP10 (coding for FKBP65) lead to a recessive form of OI, and mutations in FKBP10 are also found in Bruck syndrome and in Kuskokwim syndrome (14 -26).…”

mentioning

confidence: 99%

“…Both the enzyme activity and complex formation are important during procollagen biosynthesis. Hyperelastosis cutis, which is known as hereditary equine regional dermal asthenia, is an autosomal recessive skin fragility syndrome observed in Quarter Horses, and this disease is caused by a mutation in the protein-protein interaction site of CypB (13). This mutation does not directly affect the PPIase activity but does affect protein-protein interactions (32).…”

mentioning

confidence: 99%

“…This mutation does not directly affect the PPIase activity but does affect protein-protein interactions (32). The lack of binding to other proteins altered the post-translational modifications, rate of folding, and secretion of type I procollagen (13). The absence of CypB due to mutations or in knock-out mice results in OI with an absence of 3-hydroxylation at Pro-986 of the ␣1 chain of type I collagen (16,19,25,33).…”

mentioning

confidence: 99%

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A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

Ishikawa

Bächinger

2014

Journal of Biological Chemistry

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Background: Procollagen biosynthesis requires a large number of foldases, chaperones, and modifying enzymes. Results: FKBP22 is a foldase and chaperone that interacts with a subset of collagens. Conclusion: Collagen type-specific chaperones and foldases exist in the rER. Significance: The lack of collagen type-specific rER proteins can lead to broader or overlapping phenotypes of connective tissue disorders.

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Inherited ocular disorders

Sandmeyer

2016

Equine Ophthalmology

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Mutation in Cyclophilin B That Causes Hyperelastosis Cutis in American Quarter Horse Does Not Affect Peptidylprolyl cis-trans Isomerase Activity but Shows Altered Cyclophilin B-Protein Interactions and Affects Collagen Folding

Cited by 80 publications

References 56 publications

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

Inherited ocular disorders

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