Proteopedia

4o2e

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A peptide complexed with HLA-B*3901A peptide complexed with HLA-B*3901

Structural highlights

4o2e is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, RCSB, PDBsum

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.[1] 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.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Function

[1B39_HUMAN] Involved in the presentation of foreign antigens to the immune system. [DDX3X_HUMAN] Multifunctional ATP-dependent RNA helicase. The ATPase activity can be stimulated by various ribo- and deoxynucleic acids indicative for a relaxed substrate specificity. In vitro can unwind partially double stranded DNA with a preference for 5'-single stranded DNA overhangs. Is involved in several steps of gene expression, such as transcription, mRNA maturation, mRNA export and translation. However, the exact mechanisms are not known and some functions may be specific for a subset of mRNAs. Involved in transcriptional regulation. Can enhance transcription from the CDKN1A/WAF1 promoter in a SP1-dependent manner. Found associated with the E-cadherin promoter and can down-regulate transcription from the promoter. Involved in regulation of translation initiation. Proposed to be involved in positive regulation of translation such as of cyclin E1/CCNE1 mRNA and specifically of mRNAs containing complex secondary structures in their 5'UTRs; these functions seem to require RNA helicase activity. Specifically promotes translation of a subset of viral and cellular mRNAs carrying a 5'proximal stem-loop structure in their 5'UTRs and cooperates with the eIF4F complex. Proposed to act prior to 43S ribosomal scanning and to locally destabilize these RNA structures to allow recognition of the mRNA cap or loading onto the 40S subunit. After association with 40S ribosomal subunits seems to be involved in the functional assembly of 80S ribosomes; the function seems to cover translation of mRNAs with structured and non-structured 5'UTRs and is independent of RNA helicase activity. Also proposed to inhibit cap-dependent translation by competetive interaction with EIF4E which can block the EIF4E:EIF4G complex formation. Proposed to be involved in stress response and stress granule assembly; the function is independent of RNA helicase activity and seems to involve association with EIF4E. May be involved in nuclear export of specific mRNAs but not in bulk mRNA export via interactions with XPO1 and NXF1. Also associates with polyadenylated mRNAs independently of NXF1. Associates with spliced mRNAs in an exon junction complex (EJC)-dependent manner and seems not to be directly involved in splicing. May be involved in nuclear mRNA export by association with DDX5 and regulating its nuclear location. Involved in innate immune signaling promoting the production of type I interferon (IFN-alpha and IFN-beta); proposed to act as viral RNA sensor, signaling intermediate and transcriptional coactivator. Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFN-beta induction. Also found associated with IFN-beta promoters; the function is independent of IRF3. Can bind to viral RNAs and via association with MAVS/IPS1 and DDX58/RIG-I is thought to induce signaling in early stages of infection. Involved in regulation of apoptosis. May be required for activation of the intrinsic but inhibit activation of the extrinsic apoptotic pathway. Acts as an antiapoptotic protein through association with GSK3A/B and BIRC2 in an apoptosis antagonizing signaling complex; activation of death receptors promotes caspase-dependent cleavage of BIRC2 and DDX3X and relieves the inhibition. May be involved in mitotic chromosome segregation. Appears to be a prime target for viral manipulations. Hepatitis B virus (HBV) polymerase and possibly vaccinia virus (VACV) protein K7 inhibit IFN-beta induction probably by dissociating DDX3X from TBK1 or IKBKE. Is involved in hepatitis C virus (HCV) replication; the function may involve the association with HCV core protein. HCV core protein inhibits the IPS1-dependent function in viral RNA sensing and may switch the function from a INF-beta inducing to a HCV replication mode. Involved in HIV-1 replication. Acts as a cofactor for XPO1-mediated nuclear export of incompletely spliced HIV-1 Rev RNAs.[15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [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

As one of the most common posttranslational modifications (PTMs) of eukaryotic proteins, N(alpha)-terminal acetylation (Nt-acetylation) generates a class of N(alpha)-acetylpeptides that are known to be presented by MHC class I at the cell surface. Although such PTM plays a pivotal role in adjusting proteolysis, the molecular basis for the presentation and T cell recognition of N(alpha)-acetylpeptides remains largely unknown. In this study, we determined a high-resolution crystallographic structure of HLA (HLA)-B*3901 complexed with an N(alpha)-acetylpeptide derived from natural cellular processing, also in comparison with the unmodified-peptide complex. Unlike the alpha-amino-free P1 residues of unmodified peptide, of which the alpha-amino group inserts into pocket A of the Ag-binding groove, the N(alpha)-linked acetyl of the acetylated P1-Ser protrudes out of the groove for T cell recognition. Moreover, the Nt-acetylation not only alters the conformation of the peptide but also switches the residues in the alpha1-helix of HLA-B*3901, which may impact the T cell engagement. The thermostability measurements of complexes between N(alpha)-acetylpeptides and a series of MHC class I molecules derived from different species reveal reduced stability. Our findings provide the insight into the mode of N(alpha)-acetylpeptide-specific presentation by classical MHC class I molecules and shed light on the potential of acetylepitope-based immune intervene and vaccine development.

Nalpha-terminal acetylation for T cell recognition: molecular basis of MHC class I-restricted nalpha-acetylpeptide presentation.,Sun M, Liu J, Qi J, Tefsen B, Shi Y, Yan J, Gao GF J Immunol. 2014 Jun 15;192(12):5509-19. doi: 10.4049/jimmunol.1400199. Epub 2014 , May 14. PMID:24829406[38]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ Owsianka AM, Patel AH. Hepatitis C virus core protein interacts with a human DEAD box protein DDX3. Virology. 1999 May 10;257(2):330-40. PMID:10329544 doi:http://dx.doi.org/S0042-6822(99)99659-9
  16. ↑ Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function. Cell. 2004 Oct 29;119(3):381-92. PMID:15507209 doi:http://dx.doi.org/S0092867404008360
  17. ↑ Chao CH, Chen CM, Cheng PL, Shih JW, Tsou AP, Lee YH. DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor. Cancer Res. 2006 Jul 1;66(13):6579-88. PMID:16818630 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-2415
  18. ↑ Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH. DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control. Oncogene. 2006 Mar 30;25(14):1991-2003. PMID:16301996 doi:http://dx.doi.org/10.1038/sj.onc.1209239
  19. ↑ Franca R, Belfiore A, Spadari S, Maga G. Human DEAD-box ATPase DDX3 shows a relaxed nucleoside substrate specificity. Proteins. 2007 Jun 1;67(4):1128-37. PMID:17357160 doi:http://dx.doi.org/10.1002/prot.21433
  20. ↑ Sun M, Song L, Li Y, Zhou T, Jope RS. Identification of an antiapoptotic protein complex at death receptors. Cell Death Differ. 2008 Dec;15(12):1887-900. doi: 10.1038/cdd.2008.124. Epub 2008, Oct 10. PMID:18846110 doi:http://dx.doi.org/10.1038/cdd.2008.124
  21. ↑ Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008 Aug 6;27(15):2135-46. doi: 10.1038/emboj.2008.126. Epub 2008 Jun 26. PMID:18583960 doi:10.1038/emboj.2008.126
  22. ↑ Schroder M, Baran M, Bowie AG. Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J. 2008 Aug 6;27(15):2147-57. doi: 10.1038/emboj.2008.143. Epub 2008 Jul 17. PMID:18636090 doi:http://dx.doi.org/10.1038/emboj.2008.143
  23. ↑ Lai MC, Lee YH, Tarn WY. The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol Biol Cell. 2008 Sep;19(9):3847-58. doi: 10.1091/mbc.E07-12-1264. Epub 2008, Jul 2. PMID:18596238 doi:http://dx.doi.org/10.1091/mbc.E07-12-1264
  24. ↑ Lee CS, Dias AP, Jedrychowski M, Patel AH, Hsu JL, Reed R. Human DDX3 functions in translation and interacts with the translation initiation factor eIF3. Nucleic Acids Res. 2008 Aug;36(14):4708-18. doi: 10.1093/nar/gkn454. Epub 2008, Jul 15. PMID:18628297 doi:http://dx.doi.org/10.1093/nar/gkn454
  25. ↑ Shih JW, Tsai TY, Chao CH, Wu Lee YH. Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene. 2008 Jan 24;27(5):700-14. Epub 2007 Jul 30. PMID:17667941 doi:http://dx.doi.org/10.1038/sj.onc.1210687
  26. ↑ Botlagunta M, Vesuna F, Mironchik Y, Raman A, Lisok A, Winnard P Jr, Mukadam S, Van Diest P, Chen JH, Farabaugh P, Patel AH, Raman V. Oncogenic role of DDX3 in breast cancer biogenesis. Oncogene. 2008 Jun 26;27(28):3912-22. doi: 10.1038/onc.2008.33. Epub 2008 Feb 11. PMID:18264132 doi:http://dx.doi.org/10.1038/onc.2008.33
  27. ↑ Oshiumi H, Sakai K, Matsumoto M, Seya T. DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential. Eur J Immunol. 2010 Apr;40(4):940-8. doi: 10.1002/eji.200940203. PMID:20127681 doi:http://dx.doi.org/10.1002/eji.200940203
  28. ↑ Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z. Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon and DDX3. J Gen Virol. 2010 Aug;91(Pt 8):2080-90. doi: 10.1099/vir.0.020552-0. Epub 2010, Apr 7. PMID:20375222 doi:http://dx.doi.org/10.1099/vir.0.020552-0
  29. ↑ Lai MC, Chang WC, Shieh SY, Tarn WY. DDX3 regulates cell growth through translational control of cyclin E1. Mol Cell Biol. 2010 Nov;30(22):5444-53. doi: 10.1128/MCB.00560-10. Epub 2010 Sep , 13. PMID:20837705 doi:http://dx.doi.org/10.1128/MCB.00560-10
  30. ↑ Oshiumi H, Ikeda M, Matsumoto M, Watanabe A, Takeuchi O, Akira S, Kato N, Shimotohno K, Seya T. Hepatitis C virus core protein abrogates the DDX3 function that enhances IPS-1-mediated IFN-beta induction. PLoS One. 2010 Dec 8;5(12):e14258. doi: 10.1371/journal.pone.0014258. PMID:21170385 doi:http://dx.doi.org/10.1371/journal.pone.0014258
  31. ↑ Wang H, Ryu WS. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS Pathog. 2010 Jul 15;6(7):e1000986. doi: 10.1371/journal.ppat.1000986. PMID:20657822 doi:http://dx.doi.org/10.1371/journal.ppat.1000986
  32. ↑ Garbelli A, Beermann S, Di Cicco G, Dietrich U, Maga G. A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication. PLoS One. 2011 May 12;6(5):e19810. doi: 10.1371/journal.pone.0019810. PMID:21589879 doi:http://dx.doi.org/10.1371/journal.pone.0019810
  33. ↑ Pek JW, Kai T. DEAD-box RNA helicase Belle/DDX3 and the RNA interference pathway promote mitotic chromosome segregation. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12007-12. doi:, 10.1073/pnas.1106245108. Epub 2011 Jul 5. PMID:21730191 doi:http://dx.doi.org/10.1073/pnas.1106245108
  34. ↑ Shih JW, Wang WT, Tsai TY, Kuo CY, Li HK, Wu Lee YH. Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response. Biochem J. 2012 Jan 1;441(1):119-29. doi: 10.1042/BJ20110739. PMID:21883093 doi:http://dx.doi.org/10.1042/BJ20110739
  35. ↑ Choi YJ, Lee SG. The DEAD-box RNA helicase DDX3 interacts with DDX5, co-localizes with it in the cytoplasm during the G2/M phase of the cycle, and affects its shuttling during mRNP export. J Cell Biochem. 2012 Mar;113(3):985-96. doi: 10.1002/jcb.23428. PMID:22034099 doi:http://dx.doi.org/10.1002/jcb.23428
  36. ↑ Geissler R, Golbik RP, Behrens SE. The DEAD-box helicase DDX3 supports the assembly of functional 80S ribosomes. Nucleic Acids Res. 2012 Jun;40(11):4998-5011. doi: 10.1093/nar/gks070. Epub 2012 , Feb 9. PMID:22323517 doi:http://dx.doi.org/10.1093/nar/gks070
  37. ↑ Soto-Rifo R, Rubilar PS, Limousin T, de Breyne S, Decimo D, Ohlmann T. DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J. 2012 Sep 12;31(18):3745-56. doi: 10.1038/emboj.2012.220. Epub 2012 Aug 7. PMID:22872150 doi:http://dx.doi.org/10.1038/emboj.2012.220
  38. ↑ Sun M, Liu J, Qi J, Tefsen B, Shi Y, Yan J, Gao GF. Nalpha-terminal acetylation for T cell recognition: molecular basis of MHC class I-restricted nalpha-acetylpeptide presentation. J Immunol. 2014 Jun 15;192(12):5509-19. doi: 10.4049/jimmunol.1400199. Epub 2014 , May 14. PMID:24829406 doi:http://dx.doi.org/10.4049/jimmunol.1400199

4o2e, resolution 1.98Å

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