TY - JOUR
T1 - 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
AU - Ishikawa, Yoshihiro
AU - Vranka, Janice A.
AU - Boudko, Sergei P.
AU - Pokidysheva, Elena
AU - Mizuno, Kazunori
AU - Zientek, Keith
AU - Keene, Douglas R.
AU - Rashmir-Raven, Ann M.
AU - Nagata, Kazuhiro
AU - Winand, Nena J.
AU - Bächinger, Hans Peter
PY - 2012/6/22
Y1 - 2012/6/22
N2 - 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 cistrans 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.
AB - 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 cistrans 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.
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U2 - 10.1074/jbc.M111.333336
DO - 10.1074/jbc.M111.333336
M3 - Article
C2 - 22556420
AN - SCOPUS:84862691109
SN - 0021-9258
VL - 287
SP - 22253
EP - 22265
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -