title: 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.
abstract: The rate-limiting step of folding of the collagen triple helix is catalyzed by cyclophilin B (CypB). The G6R mutation in cyclophilin B found in the American Quarter Horse leads to autosomal recessive hyperelastosis cutis, also known as hereditary equine regional dermal asthenia. The mutant protein shows small structural changes in the region of the mutation at the side opposite the catalytic domain of CypB. The peptidylprolyl cis-trans isomerase activity of the mutant CypB is normal when analyzed in vitro. However, the biosynthesis of type I collagen in affected horse fibroblasts shows a delay in folding and secretion and a decrease in hydroxylysine and glucosyl-galactosyl hydroxylysine. This leads to changes in the structure of collagen fibrils in tendon, similar to those observed in P3H1 null mice. In contrast to cyclophilin B null mice, where little 3-hydroxylation was found in type I collagen, 3-hydroxylation of type I collagen in affected horses is normal. The mutation disrupts the interaction of cyclophilin B with the P-domain of calreticulin, with lysyl hydroxylase 1, and probably other proteins, such as the formation of the P3H1·CypB·cartilage-associated protein complex, resulting in less effective catalysis of the rate-limiting step in collagen folding in the rough endoplasmic reticulum.
authors.affiliation: Research Department, Shriners Hospital for Children, Portland, Oregon 97239, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Janice A
authors.initials: JA
authors.lastname: Vranka
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Boudko
authors.forename: Elena
authors.initials: E
authors.lastname: Pokidysheva
authors.forename: Kazunori
authors.initials: K
authors.lastname: Mizuno
authors.forename: Keith
authors.initials: K
authors.lastname: Zientek
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Ann M
authors.initials: AM
authors.lastname: Rashmir-Raven
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Nena J
authors.initials: NJ
authors.lastname: Winand
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Bächinger
mesh_terms: D000818:Animals; D001247:Asthenia; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry*; D021983:Cyclophilins / Q000235:genetics*; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism; D006736:Horses; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000737:chemistry*; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012871:Skin Diseases / Q000235:genetics* / Q000662:veterinary*; D020349:Surface Plasmon Resonance; D019745:cis-trans-Isomerases / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C081786:cyclophilin B; D003094:Collagen; D019745:cis-trans-Isomerases; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase