Crystal structures of wild-type and mutated cyclophilin B that causes hyperelastosis cutis in the American quarter horse.
Abstract: 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 disorder is caused by a mutation in cyclophilin B. Results: The 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. Conclusions: Interactions of the mutated cyclophilin B with a set of endoplasmic reticulum-resident proteins must be affected.
Publication Date: 2012-11-08 PubMed ID: 23137129PubMed Central: PMC3522003DOI: 10.1186/1756-0500-5-626Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
Summary
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This research article investigates how a genetic mutation in American Quarter Horses impacts the function of a protein called cyclophilin B, which is essential to the proper folding of collagen in the body. The resulting disease, hyperelastosis cutis, causes changes in the structure of collagen fibres in the horse’s tendon.
Mutation in Cyclophilin B
- The research examines the impact of the G6R mutation in cyclophilin B, a protein, in American Quarter Horses. This genetic mutation leads to a disease known as hyperelastosis cutis, also known as hereditary equine regional dermal asthenia (HERDA).
- The mutated protein demonstrates minor structural changes in the area of the mutation, on the side opposite to the catalytic (active) domain of cyclophilin B.
Effects on Peptidylprolyl Cis-Trans Isomerase Activity
- Despite the mutation, the peptidylprolyl cis-trans isomerase activity (the ability to accelerate the folding of proteins) of the mutant Cyclophilin B remains normal when studied in an in vitro (lab) setting.
Effects on Type I Collagen Synthesis
- However, the biosynthesis (natural production) of type I collagen in the fibroblasts (cells responsible for producing connective tissue) of the affected horses reveals a delay in protein folding and secretion.
- Additionally, there is a reduction in two compounds – hydroxylysine and glucosyl-galactosyl – hydroxylysine. As a result, there are changes in the structure of the collagen fibrils in the tendons of the horses – similar to what is observed in P3H1 null mice.
Disruption to Protein Interactions
- The mutation disrupts the interaction between cyclophilin B and other proteins such as the P-domain of calreticulin and lysyl hydroxylase 1. The mutation may also affect interactions with the P3H1·CypB·cartilage-associated protein complex.
- This results in less effective catalysis (the acceleration of a chemical reaction) of the rate-limiting step (the slowest step) in collagen folding in the rough endoplasmic reticulum (part of the cell where protein synthesis occurs).
Difference from Cyclophilin B Null Mice
- In comparison to cyclophilin B null mice, where low levels of 3-hydroxylation are found in Type I collagen, 3-hydroxylation of Type I collagen in the affected horses remains normal.
Cite This Article
APA
Boudko SP, Ishikawa Y, Lerch TF, Nix J, Chapman MS, Bächinger HP.
(2012).
Crystal structures of wild-type and mutated cyclophilin B that causes hyperelastosis cutis in the American quarter horse.
BMC Res Notes, 5, 626.
https://doi.org/10.1186/1756-0500-5-626 Publication
Researcher Affiliations
- Research Department, Shriners Hospital for Children, Portland, OR 97239, USA.
MeSH Terms
- Animals
- Crystallography, X-Ray
- Cyclophilins / chemistry
- Cyclophilins / genetics
- Horse Diseases / enzymology
- Horse Diseases / genetics
- Horses
- Models, Molecular
- Mutation, Missense
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Skin / enzymology
- Skin / metabolism
- Skin / pathology
- Skin Diseases / enzymology
- Skin Diseases / genetics
- Skin Diseases / veterinary
Grant Funding
- T32AI007472 / NIAID NIH HHS
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Citations
This article has been cited 1 times.- Ishikawa Y, Bächinger HP. A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis. J Biol Chem 2014 Jun 27;289(26):18189-201.
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