2bck

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Crystal Structure of HLA-A*2402 Complexed with a telomerase peptideCrystal Structure of HLA-A*2402 Complexed with a telomerase peptide

Structural highlights

2bck is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Activity:RNA-directed DNA polymerase, with EC number 2.7.7.49
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[TERT_HUMAN] Note=Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis. Defects in TERT are associated with susceptibilty to aplastic anemia (AA) [MIM:609135]. AA is a rare disease in which the reduction of the circulating blood cells results from damage to the stem cell pool in bone marrow. In most patients, the stem cell lesion is caused by an autoimmune attack. T-lymphocytes, activated by an endogenous or exogenous, and most often unknown antigenic stimulus, secrete cytokines, including IFN-gamma, which would in turn be able to suppress hematopoiesis.[1] [2] [3] [4] Note=Genetic variations in TERT are associated with coronary artery disease (CAD).[5] Defects in TERT are the cause of dyskeratosis congenita autosomal dominant type 2 (DKCA2) [MIM:613989]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.[6] [7] Defects in TERT are the cause of pulmonary fibrosis, and/or bone marrow failure, telomere-related, type 1 (PFBMFT1) [MIM:614742]. A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. infections, fatal pulmonary complications, or malignancy.[8] [9] [10] [11] [12] Defects in TERT are the cause of dyskeratosis congenita autosomal recessive type 4 (DKCB4) [MIM:613989]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. Defects in TERT are a cause of susceptibility to pulmonary fibrosis idiopathic (IPF) [MIM:178500]. Pulmonary fibrosis is a lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. It results in acute lung injury with subsequent scarring and endstage lung disease. [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.[13] 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.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Function

[1A24_HUMAN] Involved in the presentation of foreign antigens to the immune system. [TERT_HUMAN] Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis.[27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

HLA-A*2402 is the most commonly expressed HLA allele in oriental populations. It is also widely expressed in the Caucasian population, making it one of, if not the most abundant HLA I types. In order to study its structure in terms of overall fold and peptide presentation, a soluble form of this HLA I (alpha1, alpha2, alpha3 and beta(2)m domains) has been expressed, refolded and crystallized in complex with a cancer-related telomerase peptide (VYGFVRACL), and its structure has been solved to 2.8 A resolution. The overall structure of HLA-A*2402 is virtually identical to other reported peptide-HLA I structures. However, there are distinct features observable from this structure at the HLA I peptide binding pockets. The size and depth of pocket B makes it highly suitable for binding to large aromatic side chains, which explains the high prevalence of tyrosine at peptide position 2. Also, for HLA binding at peptide position 5, there is an additional anchor point, which allows the proximal amino acids to protrude out, providing a prominent feature for TCR interaction. Finally, pocket F allows the anchor residue at position 9 to be bound unusually deeply within the HLA structure.

Crystal structure of HLA-A*2402 complexed with a telomerase peptide.,Cole DK, Rizkallah PJ, Gao F, Watson NI, Boulter JM, Bell JI, Sami M, Gao GF, Jakobsen BK Eur J Immunol. 2006 Jan;36(1):170-9. PMID:16323248[39]

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

See Also

References

  1. ↑ Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63. PMID:15885610 doi:10.1016/j.bcmd.2004.12.008
  2. ↑ Liang J, Yagasaki H, Kamachi Y, Hama A, Matsumoto K, Kato K, Kudo K, Kojima S. Mutations in telomerase catalytic protein in Japanese children with aplastic anemia. Haematologica. 2006 May;91(5):656-8. Epub 2006 Apr 19. PMID:16627250
  3. ↑ Xin ZT, Beauchamp AD, Calado RT, Bradford JW, Regal JA, Shenoy A, Liang Y, Lansdorp PM, Young NS, Ly H. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood. 2007 Jan 15;109(2):524-32. Epub 2006 Sep 21. PMID:16990594 doi:10.1182/blood-2006-07-035089
  4. ↑ Kirwan M, Vulliamy T, Marrone A, Walne AJ, Beswick R, Hillmen P, Kelly R, Stewart A, Bowen D, Schonland SO, Whittle AM, McVerry A, Gilleece M, Dokal I. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum Mutat. 2009 Nov;30(11):1567-73. doi: 10.1002/humu.21115. PMID:19760749 doi:10.1002/humu.21115
  5. ↑ Matsubara Y, Murata M, Watanabe K, Saito I, Miyaki K, Omae K, Ishikawa M, Matsushita K, Iwanaga S, Ogawa S, Ikeda Y. Coronary artery disease and a functional polymorphism of hTERT. Biochem Biophys Res Commun. 2006 Sep 22;348(2):669-72. Epub 2006 Jul 28. PMID:16890917 doi:10.1016/j.bbrc.2006.07.103
  6. ↑ Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63. PMID:15885610 doi:10.1016/j.bcmd.2004.12.008
  7. ↑ Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4. Epub 2005 Oct 24. PMID:16247010 doi:0508124102
  8. ↑ Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005 Apr 7;352(14):1413-24. PMID:15814878 doi:10.1056/NEJMoa042980
  9. ↑ Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7. Epub 2007 Apr 25. PMID:17460043 doi:10.1073/pnas.0701009104
  10. ↑ Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011 May 26;117(21):5607-11. doi: 10.1182/blood-2010-11-322149. Epub 2011 , Mar 24. PMID:21436073 doi:10.1182/blood-2010-11-322149
  11. ↑ Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE, Lansdorp PM, Phillips JA 3rd, Loyd JE, Chen JJ, Armanios M. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet. 2011 Mar;7(3):e1001352. doi: 10.1371/journal.pgen.1001352. Epub 2011 , Mar 31. PMID:21483807 doi:10.1371/journal.pgen.1001352
  12. ↑ Gansner JM, Rosas IO, Ebert BL. Pulmonary fibrosis, bone marrow failure, and telomerase mutation. N Engl J Med. 2012 Apr 19;366(16):1551-3. doi: 10.1056/NEJMc1200999. PMID:22512499 doi:10.1056/NEJMc1200999
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 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
  27. ↑ Harrington L, Zhou W, McPhail T, Oulton R, Yeung DS, Mar V, Bass MB, Robinson MO. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev. 1997 Dec 1;11(23):3109-15. PMID:9389643
  28. ↑ Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res. 2004 Apr 2;94(6):768-75. Epub 2004 Feb 12. PMID:14963003 doi:10.1161/01.RES.0000121104.05977.F3
  29. ↑ Moriarty TJ, Marie-Egyptienne DT, Autexier C. Functional organization of repeat addition processivity and DNA synthesis determinants in the human telomerase multimer. Mol Cell Biol. 2004 May;24(9):3720-33. PMID:15082768
  30. ↑ Moriarty TJ, Ward RJ, Taboski MA, Autexier C. An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization. Mol Biol Cell. 2005 Jul;16(7):3152-61. Epub 2005 Apr 27. PMID:15857955 doi:10.1091/mbc.E05-02-0148
  31. ↑ Rahman R, Mo L, Cui W. Telomerase with mutated catalytic motifs has dominant negative effects on telomerase activity and inhibits cell growth. Biochem Biophys Res Commun. 2006 Nov 24;350(3):796-802. Epub 2006 Sep 29. PMID:17026956 doi:10.1016/j.bbrc.2006.09.125
  32. ↑ Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007 Jun 15;178(12):7710-9. PMID:17548608
  33. ↑ Wyatt HD, Lobb DA, Beattie TL. Characterization of physical and functional anchor site interactions in human telomerase. Mol Cell Biol. 2007 Apr;27(8):3226-40. Epub 2007 Feb 12. PMID:17296728 doi:10.1128/MCB.02368-06
  34. ↑ Drosopoulos WC, Prasad VR. The active site residue Valine 867 in human telomerase reverse transcriptase influences nucleotide incorporation and fidelity. Nucleic Acids Res. 2007;35(4):1155-68. Epub 2007 Jan 30. PMID:17264120 doi:10.1093/nar/gkm002
  35. ↑ Ram R, Uziel O, Eldan O, Fenig E, Beery E, Lichtenberg S, Nordenberg Y, Lahav M. Ionizing radiation up-regulates telomerase activity in cancer cell lines by post-translational mechanism via ras/phosphatidylinositol 3-kinase/Akt pathway. Clin Cancer Res. 2009 Feb 1;15(3):914-23. doi: 10.1158/1078-0432.CCR-08-0792. PMID:19188162 doi:10.1158/1078-0432.CCR-08-0792
  36. ↑ Oh W, Ghim J, Lee EW, Yang MR, Kim ET, Ahn JH, Song J. PML-IV functions as a negative regulator of telomerase by interacting with TERT. J Cell Sci. 2009 Aug 1;122(Pt 15):2613-22. doi: 10.1242/jcs.048066. Epub 2009 Jun, 30. PMID:19567472 doi:10.1242/jcs.048066
  37. ↑ Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72. doi: 10.1038/nature08137. PMID:19571879 doi:10.1038/nature08137
  38. ↑ Wyatt HD, Tsang AR, Lobb DA, Beattie TL. Human telomerase reverse transcriptase (hTERT) Q169 is essential for telomerase function in vitro and in vivo. PLoS One. 2009 Sep 24;4(9):e7176. doi: 10.1371/journal.pone.0007176. PMID:19777057 doi:10.1371/journal.pone.0007176
  39. ↑ Cole DK, Rizkallah PJ, Gao F, Watson NI, Boulter JM, Bell JI, Sami M, Gao GF, Jakobsen BK. Crystal structure of HLA-A*2402 complexed with a telomerase peptide. Eur J Immunol. 2006 Jan;36(1):170-9. PMID:16323248 doi:http://dx.doi.org/10.1002/eji.200535424

2bck, resolution 2.80Å

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