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
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research investigates the changes in a mutated version of a protein called cyclophilin B in American quarter horses with an inherited skin condition called hyperelastosis cutis. The scientists found that the mutation does not affect the overall shape or function of the enzyme but does cause local changes and stiffness in a section of the protein chain.
Objective and Methodology
- The researchers set out to compare the structure of a naturally occurring cyclophilin B enzyme with a mutated form responsible for the connective tissue disorder hyperelastosis cutis in American quarter horses.
- To do this, they used crystallography to determine the detailed atomic structure of both the normal (wild-type) and mutated versions of the enzyme.
Structural Findings
- Despite the inherited mutation (where a glycine molecule at position 6 is replaced by an arginine molecule), the researchers found the overall fold of the enzyme remained unaffected. This suggests the fundamental structure and function of the enzyme are preserved.
- The catalytic site — the part of the enzyme responsible for accelerating chemical reactions — was also found to be unimpaired by the mutation.
- However, the mutation induced local rearrangements and increased rigidity at the flexible N-terminal region of the enzyme, a section of the polypeptide chain responsible for protein interactions and functions.
Conclusions and Implications
- The researchers concluded that the mutation might affect the interactions between cyclophilin B and various proteins residing in the endoplasmic reticulum — an organelle that aids in the production, processing, and transport of proteins.
- This disruption of normal protein interactions offers a potential explanation for the dermal symptoms observed in the afflicted horses, including skin hyperextensibility, scarring, and severe lesions.
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
References
This article includes 22 references
- White SD, Affolter VK, Bannasch DL, Schultheiss PC, Hamar DW, Chapman PL, Naydan D, Spier SJ, Rosychuk RA, Rees C. Hereditary equine regional dermal asthenia (“hyperelastosis cutis”) in 50 horses: clinical, histological, immunohistological and ultrastructural findings.. Vet Dermatol 2004;15(4):207–217.
- Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens.. J Clin Invest 2001;107(9):1063–1069.
- Tryon RC, White SD, Bannasch DL. Homozygosity mapping approach identifies a missense mutation in equine cyclophilin B (PPIB) associated with HERDA in the American Quarter Horse.. Genomics 2007;90(1):93–102.
- Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence.. Proc Natl Acad Sci USA 1991;88(5):1903–1907.
- Hasel KW, Glass JR, Godbout M, Sutcliffe JG. An endoplasmic reticulum-specific cyclophilin.. Mol Cell Biol 1991;11(7):3484–3491.
- Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase.. J Biol Chem 1991;266(2):1299–1303.
- van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, Jimenez CR, Huizer M, Morsman AC, Cobben JM. PPIB mutations cause severe osteogenesis imperfecta.. Am J Hum Genet 2009;85(4):521–527.
- Choi JW, Sutor SL, Lindquist L, Evans GL, Madden BJ, Bergen HR 3rd, Hefferan TE, Yaszemski MJ, Bram RJ. Severe osteogenesis imperfecta in cyclophilin B-deficient mice.. PLoS Genet 2009;5(12):e1000750.
- Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta.. Nat Rev Endocrinol 2011;7(9):540–557.
- Vranka JA, Sakai LY, Bächinger HP. Prolyl 3-hydroxylase 1, enzyme characterization and identification of a novel family of enzymes.. J Biol Chem 2004;279(22):23615–23621.
- Ishikawa Y, Wirz J, Vranka JA, Nagata K, Bächinger HP. Biochemical characterization of the prolyl 3-hydroxylase 1.cartilage-associated protein.cyclophilin B complex.. J Biol Chem 2009;284(26):17641–17647.
- Braakman I, Bulleid NJ. Protein folding and modification in the mammalian endoplasmic reticulum.. Annu Rev Biochem 2011;80:71–99.
- Jansen G, Maattanen P, Denisov AY, Scarffe L, Schade B, Balghi H, Dejgaard K, Chen LY, Muller WJ, Gehring K. An interaction map of ER chaperones and foldases.. Mol Cell Proteomics 2012;11(9):710–723.
- Kozlov G, Bastos-Aristizabal S, Maattanen P, Rosenauer A, Zheng F, Killikelly A, Trempe JF, Thomas DY, Gehring K. Structural basis of cyclophilin B binding by the calnexin/calreticulin P-domain.. J Biol Chem 2010;285(46):35551–35557.
- Ishikawa Y, Vranka JA, Boudko SP, Pokidysheva E, Mizuno K, Zientek K, Keene DR, Rashmir-Raven AM, Nagata K, Winand NJ. The mutation in cyclophilin B that causes hyperelastosis cutis in the American Quarter Horse does not affect peptidyl-prolyl cis-trans isomerase activity, but shows altered cyclophilin B-protein interactions and affects collagen folding.. J Biol Chem 2012;287:22253–22265.
- Pehar M, Lehnus M, Karst A, Puglielli L. Proteomic assessment shows that many endoplasmic reticulum (ER)-resident proteins are targeted by N(epsilon)-lysine acetylation in the lumen of the organelle and predicts broad biological impact.. J Biol Chem 2012;287(27):22436–22440.
- Collaborative Computational Project N. The CCP4 suite: programs for protein crystallography.. Acta Crystallogr D: Biol Crystallogr 1994;50(Pt 5):760–763.
- Mikol V, Kallen J, Walkinshaw MD. X-ray structure of a cyclophilin B/cyclosporin complex: comparison with cyclophilin A and delineation of its calcineurin-binding domain.. Proc Natl Acad Sci USA 1994;91(11):5183–5186.
- Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot.. Acta Crystallogr D: Biol Crystallogr 2010;66(Pt 4):486–501.
- Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW. PHENIX: a comprehensive Python-based system for macromolecular structure solution.. Acta Crystallogr D: Biol Crystallogr 2010;66(Pt 2):213–221.
- McNicholas S, Potterton E, Wilson KS, Noble ME. Presenting your structures: the CCP4mg molecular-graphics software.. Acta Crystallogr D: Biol Crystallogr 2011;67(Pt 4):386–394.
- Chen VB, Arendall WB 3rd, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC. MolProbity: all-atom structure validation for macromolecular crystallography.. Acta Crystallogr D Biol Crystallogr 2010;66(Pt 1):12–21.
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.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
