Proteopedia

2xpg

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Crystal structure of a MHC class I-peptide complexCrystal structure of a MHC class I-peptide complex

Structural highlights

2xpg is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MYPR_HUMAN] Defects in PLP1 are the cause of leukodystrophy hypomyelinating type 1 (HLD1) [MIM:312080]; also known as Pelizaeus-Merzbacher disease. HLD1 is an X-linked recessive dysmyelinating disorder of the central nervous system in which myelin is not formed properly. It is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] Defects in PLP1 are the cause of spastic paraplegia X-linked type 2 (SPG2) [MIM:312920]. SPG2 is characterized by spastic gait and hyperreflexia. In some patients, complicating features include nystagmus, dysarthria, sensory disturbance, mental retardation, optic atrophy.[31] [32] [33] [34] [35] [36] [37] [38] [39] [B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[40] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53]

Function

[1A03_HUMAN] Involved in the presentation of foreign antigens to the immune system. [MYPR_HUMAN] This is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin. [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.

Publication Abstract from PubMed

The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 A resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis.,McMahon RM, Friis L, Siebold C, Friese MA, Fugger L, Jones EY Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):447-54. Epub 2011 Apr 13. PMID:21543847[54]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Hudson LD, Puckett C, Berndt J, Chan J, Gencic S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8128-31. PMID:2479017
  2. ↑ Gencic S, Abuelo D, Ambler M, Hudson LD. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet. 1989 Sep;45(3):435-42. PMID:2773936
  3. ↑ Trofatter JA, Dlouhy SR, DeMyer W, Conneally PM, Hodes ME. Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9427-30. PMID:2480601
  4. ↑ Weimbs T, Dick T, Stoffel W, Boltshauser E. A point mutation at the X-chromosomal proteolipid protein locus in Pelizaeus-Merzbacher disease leads to disruption of myelinogenesis. Biol Chem Hoppe Seyler. 1990 Dec;371(12):1175-83. PMID:1708672
  5. ↑ Pratt VM, Trofatter JA, Schinzel A, Dlouhy SR, Conneally PM, Hodes ME. A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease. Am J Med Genet. 1991 Jan;38(1):136-9. PMID:1707231 doi:http://dx.doi.org/10.1002/ajmg.1320380129
  6. ↑ Pham-Dinh D, Popot JL, Boespflug-Tanguy O, Landrieu P, Deleuze JF, Boue J, Jolles P, Dautigny A. Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7562-6. PMID:1715570
  7. ↑ Doll R, Natowicz MR, Schiffmann R, Smith FI. Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease. Am J Hum Genet. 1992 Jul;51(1):161-9. PMID:1376966
  8. ↑ Strautnieks S, Rutland P, Winter RM, Baraitser M, Malcolm S. Pelizaeus-Merzbacher disease: detection of mutations Thr181----Pro and Leu223----Pro in the proteolipid protein gene, and prenatal diagnosis. Am J Hum Genet. 1992 Oct;51(4):871-8. PMID:1384324
  9. ↑ Pratt VM, Kiefer JR, Lahdetie J, Schleutker J, Hodes ME, Dlouhy SR. Linkage of a new mutation in the proteolipid protein (PLP) gene to Pelizaeus-Merzbacher disease (PMD) in a large Finnish kindred. Am J Hum Genet. 1993 Jun;52(6):1053-6. PMID:7684886
  10. ↑ Otterbach B, Stoffel W, Ramaekers V. A novel mutation in the proteolipid protein gene leading to Pelizaeus-Merzbacher disease. Biol Chem Hoppe Seyler. 1993 Jan;374(1):75-83. PMID:7679906
  11. ↑ Iwaki A, Muramoto T, Iwaki I, Furumi H, Dario-deLeon ML, Tateishi J, Fukumaki Y. A missense mutation in the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease in a Japanese family. Hum Mol Genet. 1993 Jan;2(1):19-22. PMID:7683951
  12. ↑ Schaid DJ, Sommer SS. Comparison of statistics for candidate-gene association studies using cases and parents. Am J Hum Genet. 1994 Aug;55(2):402-9. PMID:8037216
  13. ↑ Kleindorfer DO, Dlouhy SR, Pratt VM, Jones MC, Trofatter JA, Hodes ME. In-frame deletion in the proteolipid protein gene of a family with Pelizaeus-Merzbacher disease. Am J Med Genet. 1995 Feb 13;55(4):405-7. PMID:7539213 doi:http://dx.doi.org/10.1002/ajmg.1320550404
  14. ↑ Pratt VM, Boyadjiev S, Green K, Hodes ME, Dlouhy SR. Pelizaeus-Merzbacher disease caused by a de novo mutation that originated in exon 2 of the maternal great-grandfather of the propositus. Am J Med Genet. 1995 Jul 31;58(1):70-3. PMID:7573159 doi:http://dx.doi.org/10.1002/ajmg.1320580114
  15. ↑ Pratt VM, Dlouhy SR, Hodes ME. Pelizaeus-Merzbacher disease: a point mutation in exon 6 of the proteolipid protein (PLP) gene. Clin Genet. 1995 Feb;47(2):99-100. PMID:7541731
  16. ↑ Pratt VM, Naidu S, Dlouhy SR, Marks HG, Hodes ME. A novel mutation in exon 3 of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology. 1995 Feb;45(2):394-5. PMID:7531827
  17. ↑ Nance MA, Boyadjiev S, Pratt VM, Taylor S, Hodes ME, Dlouhy SR. Adult-onset neurodegenerative disorder due to proteolipid protein gene mutation in the mother of a man with Pelizaeus-Merzbacher disease. Neurology. 1996 Nov;47(5):1333-5. PMID:8909455
  18. ↑ Kawanishi C, Osaka H, Owa K, Inoue K, Miyakawa T, Onishi H, Yamada Y, Suzuki K, Kimura S, Kosaka K. A new missense mutation in exon 6 of the proteolipid protein gene in a patient with Pelizaeus-Merzbacher disease. Hum Mutat. 1997;9(5):475-6. PMID:9143933 doi:<475::AID-HUMU19>3.0.CO;2-# 10.1002/(SICI)1098-1004(1997)9:5<475::AID-HUMU19>3.0.CO;2-#
  19. ↑ Inoue K, Osaka H, Kawanishi C, Sugiyama N, Ishii M, Sugita K, Yamada Y, Kosaka K. Mutations in the proteolipid protein gene in Japanese families with Pelizaeus-Merzbacher disease. Neurology. 1997 Jan;48(1):283-5. PMID:9008538
  20. ↑ Yamamoto T, Nanba E, Zhang H, Sasaki M, Komaki H, Takeshita K. Jimpy(msd) mouse mutation and connatal Pelizaeus-Merzbacher disease. Am J Med Genet. 1998 Feb 3;75(4):439-40. PMID:9482656
  21. ↑ Hodes ME, Aydanian A, Dlouhy SR, Whelan DT, Heshka T, Ronen G. A de novo mutation (C755T; Ser252Phe) in exon 6 of the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease. Clin Genet. 1998 Sep;54(3):248-9. PMID:9788732
  22. ↑ Nagao M, Kadowaki J. Connatal Pelizaeus-Merzbacher disease: a missense mutation in exon 4 of the proteolipid protein (PLP) gene. J Hum Genet. 1998;43(3):206-8. PMID:9747038 doi:10.1007/s100380050072
  23. ↑ Sistermans EA, de Coo RF, De Wijs IJ, Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology. 1998 Jun;50(6):1749-54. PMID:9633722
  24. ↑ Mimault C, Giraud G, Courtois V, Cailloux F, Boire JY, Dastugue B, Boespflug-Tanguy O. Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease. Am J Hum Genet. 1999 Aug;65(2):360-9. PMID:10417279
  25. ↑ Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, Barker B, Aleck KA, Hurley TD, Dlouhy SR. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet. 1999 Jan 15;82(2):132-9. PMID:9934976
  26. ↑ Osaka H, Kawanishi C, Inoue K, Onishi H, Kobayashi T, Sugiyama N, Kosaka K, Nezu A, Fujii K, Sugita K, Kodama K, Murayama K, Murayama S, Kanazawa I, Kimura S. Pelizaeus-Merzbacher disease: three novel mutations and implication for locus heterogeneity. Ann Neurol. 1999 Jan;45(1):59-64. PMID:9894878
  27. ↑ Yamamoto T, Nanba E. A novel mutation (A246T) in exon 6 of the proteolipid protein gene associated with connatal Pelizaeus-Merzbacher disease. Hum Mutat. 1999 Aug 19;14(2):182. PMID:10425042 doi:<182::AID-HUMU12>3.0.CO;2-Y 10.1002/(SICI)1098-1004(1999)14:2<182::AID-HUMU12>3.0.CO;2-Y
  28. ↑ Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V, Giraud G, Dastugue B, Boespflug-Tanguy O. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet. 2000 Nov;8(11):837-45. PMID:11093273 doi:10.1038/sj.ejhg.5200537
  29. ↑ Seeman P, Paderova K, Benes V Jr, Sistermans EA. A severe connatal form of Pelizaeus Merzbacher disease in a Czech boy caused by a novel mutation (725C>A, Ala242Glu) at the 'jimpy(msd) codon' in the PLP gene. Int J Mol Med. 2002 Feb;9(2):125-9. PMID:11786921
  30. ↑ Hubner CA, Orth U, Senning A, Steglich C, Kohlschutter A, Korinthenberg R, Gal A. Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease. Hum Mutat. 2005 Mar;25(3):321-2. PMID:15712223 doi:10.1002/humu.9314
  31. ↑ Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V, Giraud G, Dastugue B, Boespflug-Tanguy O. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet. 2000 Nov;8(11):837-45. PMID:11093273 doi:10.1038/sj.ejhg.5200537
  32. ↑ Saugier-Veber P, Munnich A, Bonneau D, Rozet JM, Le Merrer M, Gil R, Boespflug-Tanguy O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994 Mar;6(3):257-62. PMID:8012387 doi:http://dx.doi.org/10.1038/ng0394-257
  33. ↑ Kobayashi H, Hoffman EP, Marks HG. The rumpshaker mutation in spastic paraplegia. Nat Genet. 1994 Jul;7(3):351-2. PMID:7522741 doi:http://dx.doi.org/10.1038/ng0794-351
  34. ↑ Donnelly A, Colley A, Crimmins D, Mulley J. A novel mutation in exon 6 (F236S) of the proteolipid protein gene is associated with spastic paraplegia. Hum Mutat. 1996;8(4):384-5. PMID:8956049 doi:<384::AID-HUMU17>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:4<384::AID-HUMU17>3.0.CO;2-Z
  35. ↑ Cambi F, Tang XM, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. Neurology. 1996 Apr;46(4):1112-7. PMID:8780101
  36. ↑ Hodes ME, Hadjisavvas A, Butler IJ, Aydanian A, Dlouhy SR. X-linked spastic paraplegia due to a mutation (C506T; Ser169Phe) in exon 4 of the proteolipid protein gene (PLP). Am J Med Genet. 1998 Feb 17;75(5):516-7. PMID:9489796
  37. ↑ Sivakumar K, Sambuughin N, Selenge B, Nagle JW, Baasanjav D, Hudson LD, Goldfarb LG. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol. 1999 May;45(5):680-3. PMID:10319897
  38. ↑ Lee ES, Moon HK, Park YH, Garbern J, Hobson GM. A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. J Neurol Sci. 2004 Sep 15;224(1-2):83-7. PMID:15450775 doi:10.1016/j.jns.2004.05.015
  39. ↑ Gorman MP, Golomb MR, Walsh LE, Hobson GM, Garbern JY, Kinkel RP, Darras BT, Urion DK, Eksioglu YZ. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology. 2007 Apr 17;68(16):1305-7. PMID:17438221 doi:10.1212/01.wnl.0000259522.49388.53
  40. ↑ Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S, Waldmann TA, Robinson JM, Anderson CL. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5084-9. Epub 2006 Mar 20. PMID:16549777 doi:10.1073/pnas.0600548103
  41. ↑ Gorevic PD, Munoz PC, Casey TT, DiRaimondo CR, Stone WJ, Prelli FC, Rodrigues MM, Poulik MD, Frangione B. Polymerization of intact beta 2-microglobulin in tissue causes amyloidosis in patients on chronic hemodialysis. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7908-12. PMID:3532124
  42. ↑ Argiles A, Derancourt J, Jauregui-Adell J, Mion C, Demaille JG. Biochemical characterization of serum and urinary beta 2 microglobulin in end-stage renal disease patients. Nephrol Dial Transplant. 1992;7(11):1106-10. PMID:1336137
  43. ↑ Momoi T, Suzuki M, Titani K, Hisanaga S, Ogawa H, Saito A. Amino acid sequence of a modified beta 2-microglobulin in renal failure patient urine and long-term dialysis patient blood. Clin Chim Acta. 1995 May 15;236(2):135-44. PMID:7554280
  44. ↑ Cunningham BA, Wang JL, Berggard I, Peterson PA. The complete amino acid sequence of beta 2-microglobulin. Biochemistry. 1973 Nov 20;12(24):4811-22. PMID:4586824
  45. ↑ Haag-Weber M, Mai B, Horl WH. Isolation of a granulocyte inhibitory protein from uraemic patients with homology of beta 2-microglobulin. Nephrol Dial Transplant. 1994;9(4):382-8. PMID:8084451
  46. ↑ Trinh CH, Smith DP, Kalverda AP, Phillips SE, Radford SE. Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9771-6. Epub 2002 Jul 15. PMID:12119416 doi:10.1073/pnas.152337399
  47. ↑ Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol. 2003 Jul;4(7):657-63. Epub 2003 Jun 8. PMID:12796775 doi:10.1038/ni942
  48. ↑ Kihara M, Chatani E, Iwata K, Yamamoto K, Matsuura T, Nakagawa A, Naiki H, Goto Y. Conformation of amyloid fibrils of beta2-microglobulin probed by tryptophan mutagenesis. J Biol Chem. 2006 Oct 13;281(41):31061-9. Epub 2006 Aug 10. PMID:16901902 doi:10.1074/jbc.M605358200
  49. ↑ Eakin CM, Berman AJ, Miranker AD. A native to amyloidogenic transition regulated by a backbone trigger. Nat Struct Mol Biol. 2006 Mar;13(3):202-8. Epub 2006 Feb 19. PMID:16491088 doi:10.1038/nsmb1068
  50. ↑ Iwata K, Matsuura T, Sakurai K, Nakagawa A, Goto Y. High-resolution crystal structure of beta2-microglobulin formed at pH 7.0. J Biochem. 2007 Sep;142(3):413-9. Epub 2007 Jul 23. PMID:17646174 doi:10.1093/jb/mvm148
  51. ↑ Ricagno S, Colombo M, de Rosa M, Sangiovanni E, Giorgetti S, Raimondi S, Bellotti V, Bolognesi M. DE loop mutations affect beta2-microglobulin stability and amyloid aggregation. Biochem Biophys Res Commun. 2008 Dec 5;377(1):146-50. Epub 2008 Oct 1. PMID:18835253 doi:S0006-291X(08)01866-4
  52. ↑ Esposito G, Ricagno S, Corazza A, Rennella E, Gumral D, Mimmi MC, Betto E, Pucillo CE, Fogolari F, Viglino P, Raimondi S, Giorgetti S, Bolognesi B, Merlini G, Stoppini M, Bolognesi M, Bellotti V. The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties. J Mol Biol. 2008 May 9;378(4):887-97. Epub 2008 Mar 8. PMID:18395224 doi:10.1016/j.jmb.2008.03.002
  53. ↑ Ricagno S, Raimondi S, Giorgetti S, Bellotti V, Bolognesi M. Human beta-2 microglobulin W60V mutant structure: Implications for stability and amyloid aggregation. Biochem Biophys Res Commun. 2009 Mar 13;380(3):543-7. Epub 2009 Jan 25. PMID:19284997 doi:10.1016/j.bbrc.2009.01.116
  54. ↑ McMahon RM, Friis L, Siebold C, Friese MA, Fugger L, Jones EY. Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis. Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):447-54. Epub 2011 Apr 13. PMID:21543847 doi:10.1107/S0907444911007888

2xpg, resolution 2.60Å

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