Crystal structures of wild-type and mutated cyclophilin B that causes hyperelastosis cutis in the American quarter horse

BMC Research Notes

Hans Peter Bächinger²  Michael S Chapman²  Jay Nix¹  Thomas F Lerch²  Yoshihiro Ishikawa²  Sergei P Boudko² 

[1] Molecular Biology Consortium, Advanced Light Source Beamline 4.2.2, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA;Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA

关键词: HERDA;    Collagen;    Lysyl hydroxylase;    P-domain;    Calreticulin;    Protein complex;    Chaperone;    Endoplasmic reticulum;    Cyclophilin B (CypB);    Peptidyl prolyl cis-trans-isomerase (PPIase);   

Others  :  1165254
DOI  :  10.1186/1756-0500-5-626

 received in 2012-09-20, accepted in 2012-11-01,  发布年份 2012

【 摘 要 】

Background

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.

【 授权许可】

   
2012 Boudko et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]White SD, Affolter VK, Bannasch DL, Schultheiss PC, Hamar DW, Chapman PL, Naydan D, Spier SJ, Rosychuk RA, Rees C, et al.: Hereditary equine regional dermal asthenia (“hyperelastosis cutis”) in 50 horses: clinical, histological, immunohistological and ultrastructural findings. Vet Dermatol 2004, 15(4):207-217.
• [2]Mao JR, Bristow J: The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest 2001, 107(9):1063-1069.
• [3]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.
• [4]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.
• [5]Hasel KW, Glass JR, Godbout M, Sutcliffe JG: An endoplasmic reticulum-specific cyclophilin. Mol Cell Biol 1991, 11(7):3484-3491.
• [6]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.
• [7]van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, Jimenez CR, Huizer M, Morsman AC, Cobben JM, et al.: PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 2009, 85(4):521-527.
• [8]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.
• [9]Forlino A, Cabral WA, Barnes AM, Marini JC: New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 2011, 7(9):540-557.
• [10]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.
• [11]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.
• [12]Braakman I, Bulleid NJ: Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem 2011, 80:71-99.
• [13]Jansen G, Maattanen P, Denisov AY, Scarffe L, Schade B, Balghi H, Dejgaard K, Chen LY, Muller WJ, Gehring K, et al.: An interaction map of ER chaperones and foldases. Mol Cell Proteomics 2012, 11(9):710-723.
• [14]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.
• [15]Ishikawa Y, Vranka JA, Boudko SP, Pokidysheva E, Mizuno K, Zientek K, Keene DR, Rashmir-Raven AM, Nagata K, Winand NJ, et al.: 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.
• [16]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.
• [17]Collaborative Computational Project N: The CCP4 suite: programs for protein crystallography. Acta Crystallogr D: Biol Crystallogr 1994, 50(Pt 5):760-763.
• [18]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.
• [19]Emsley P, Lohkamp B, Scott WG, Cowtan K: Features and development of Coot. Acta Crystallogr D: Biol Crystallogr 2010, 66(Pt 4):486-501.
• [20]Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, et al.: PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D: Biol Crystallogr 2010, 66(Pt 2):213-221.
• [21]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.
• [22]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.