Abstract
BackgroundHyperelastosis cutis is an inherited autosomal recessive connective tissue disorder. Affected horses are characterized by hyperextensible skin, scarring, and severe lesions along the back. The disorder is caused by a mutation in cyclophilin B.ResultsThe crystal structures of both wild-type and mutated (Gly6->Arg) horse cyclophilin B are presented. The mutation neither affects the overall fold of the enzyme nor impairs the catalytic site structure. Instead, it locally rearranges the flexible N-terminal end of the polypeptide chain and also makes it more rigid.ConclusionsInteractions of the mutated cyclophilin B with a set of endoplasmic reticulum-resident proteins must be affected.
Highlights
Hyperelastosis cutis is an inherited autosomal recessive connective tissue disorder
The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins like cyclophilin B (CypB) which interact with type I procollagen during post-translational modification and/or folding [9]
The presence of two recombinantly added amino acids (Ala-Met) preceding the natural sequence in our constructs of both Hyperelastosis cutis (HC) and normal CypB accounts for a partial stabilization of the N-terminal segment via charge/polar contacts of Ala (−1) with His133 of a neighbor molecule and hydrophobic environment for Met0 formed by residues Met68, Ala108 and Phe120 of the adjacent molecule
Summary
Hyperelastosis cutis is an inherited autosomal recessive connective tissue disorder. Affected horses are characterized by hyperextensible skin, scarring, and severe lesions along the back. The mutation neither affects the overall fold of the enzyme nor impairs the catalytic site structure. Instead, it locally rearranges the flexible N-terminal end of the polypeptide chain and makes it more rigid. CypB plays a significant role in the triple helix folding of collagen [6] It catalyzes the slow cis-trans isomerization of multiple proline residues in the collagen chain. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins like CypB which interact with type I procollagen during post-translational modification and/or folding [9]. CypB forms a complex with prolyl 3-hydroxylase and cartilage-associated protein [10]
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