| Structural highlights
3bgm 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.
| | Ligands: | |
| NonStd Res: | |
| Related: | 3bh8, 3bh9, 3bha, 3bhb |
| Gene: | HLA-A, HLAA (HUMAN), B2M (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
[1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [KPCD2_HUMAN] Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress-induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. May potentiate mitogenesis induced by the neuropeptide bombesin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. In response to oxidative stress, is phosphorylated at Tyr-438 by ABL1, which leads to the activation of PRKD2 without increasing its catalytic activity, and mediates activation of NF-kappa-B. In response to the activation of the gastrin receptor CCKBR, is phosphorylated at Ser-244 by CSNK1D and CSNK1E, translocates to the nucleus, phosphorylates HDAC7, leading to nuclear export of HDAC7 and inhibition of HDAC7 transcriptional repression of NR4A1/NUR77. Upon TCR stimulation, is activated independently of ZAP70, translocates from the cytoplasm to the nucleus and is required for interleukin-2 (IL2) promoter up-regulation. During adaptive immune responses, is required in peripheral T-lymphocytes for the production of the effector cytokines IL2 and IFNG after TCR engagement and for optimal induction of antibody responses to antigens. In epithelial cells stimulated with lysophosphatidic acid (LPA), is activated through a PKC-dependent pathway and mediates LPA-stimulated interleukin-8 (IL8) secretion via a NF-kappa-B-dependent pathway. During TCR-induced T-cell activation, interacts with and is activated by the tyrosine kinase LCK, which results in the activation of the NFAT transcription factors. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane and in polarized cells is involved in the transport of proteins from the TGN to the basolateral membrane. Plays an important role in endothelial cell proliferation and migration prior to angiogenesis, partly through modulation of the expression of KDR/VEGFR2 and FGFR1, two key growth factor receptors involved in angiogenesis. In secretory pathway, is required for the release of chromogranin-A (CHGA)-containing secretory granules from the TGN. Downstream of PRKCA, plays important roles in angiotensin-2-induced monocyte adhesion to endothelial cells.[15] [16] [17] [18] [19] [20] [21] [22] [23] [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
Protein phosphorylation generates a source of phosphopeptides that are presented by major histocompatibility complex class I molecules and recognized by T cells. As deregulated phosphorylation is a hallmark of malignant transformation, the differential display of phosphopeptides on cancer cells provides an immunological signature of 'transformed self'. Here we demonstrate that phosphorylation can considerably increase peptide binding affinity for HLA-A2. To understand this, we solved crystal structures of four phosphopeptide-HLA-A2 complexes. These identified a novel peptide-binding motif centered on a solvent-exposed phosphate anchor. Our findings indicate that deregulated phosphorylation can create neoantigens by promoting binding to major histocompatibility complex molecules or by affecting the antigenic identity of presented epitopes. These results highlight the potential of phosphopeptides as novel targets for cancer immunotherapy.
Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self.,Mohammed F, Cobbold M, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Engelhard VH, Willcox BE Nat Immunol. 2008 Nov;9(11):1236-43. Epub 2008 Oct 5. PMID:18836451[24]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Mihailovic T, Marx M, Auer A, Van Lint J, Schmid M, Weber C, Seufferlein T. Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells. Cancer Res. 2004 Dec 15;64(24):8939-44. PMID:15604256 doi:10.1158/0008-5472.CAN-04-0981
- ↑ Yeaman C, Ayala MI, Wright JR, Bard F, Bossard C, Ang A, Maeda Y, Seufferlein T, Mellman I, Nelson WJ, Malhotra V. Protein kinase D regulates basolateral membrane protein exit from trans-Golgi network. Nat Cell Biol. 2004 Feb;6(2):106-12. Epub 2004 Jan 25. PMID:14743217 doi:10.1038/ncb1090
- ↑ Irie A, Harada K, Tsukamoto H, Kim JR, Araki N, Nishimura Y. Protein kinase D2 contributes to either IL-2 promoter regulation or induction of cell death upon TCR stimulation depending on its activity in Jurkat cells. Int Immunol. 2006 Dec;18(12):1737-47. Epub 2006 Oct 31. PMID:17077180 doi:10.1093/intimm/dxl108
- ↑ Chiu TT, Leung WY, Moyer MP, Strieter RM, Rozengurt E. Protein kinase D2 mediates lysophosphatidic acid-induced interleukin 8 production in nontransformed human colonic epithelial cells through NF-kappaB. Am J Physiol Cell Physiol. 2007 Feb;292(2):C767-77. Epub 2006 Aug 23. PMID:16928771 doi:10.1152/ajpcell.00308.2006
- ↑ von Blume J, Knippschild U, Dequiedt F, Giamas G, Beck A, Auer A, Van Lint J, Adler G, Seufferlein T. Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. EMBO J. 2007 Nov 14;26(22):4619-33. Epub 2007 Oct 25. PMID:17962809 doi:10.1038/sj.emboj.7601891
- ↑ Ge X, Low B, Liang M, Fu J. Angiotensin II directly triggers endothelial exocytosis via protein kinase C-dependent protein kinase D2 activation. J Pharmacol Sci. 2007 Oct;105(2):168-76. PMID:17951978
- ↑ von Wichert G, Edenfeld T, von Blume J, Krisp H, Krndija D, Schmid H, Oswald F, Lother U, Walther P, Adler G, Seufferlein T. Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells. Cell Signal. 2008 May;20(5):925-34. doi: 10.1016/j.cellsig.2008.01.003. Epub 2008, Jan 16. PMID:18262756 doi:10.1016/j.cellsig.2008.01.003
- ↑ Li Q, Sun X, Wu J, Lin Z, Luo Y. PKD2 interacts with Lck and regulates NFAT activity in T cells. BMB Rep. 2009 Jan 31;42(1):35-40. PMID:19192391
- ↑ Hao Q, Wang L, Zhao ZJ, Tang H. Identification of protein kinase D2 as a pivotal regulator of endothelial cell proliferation, migration, and angiogenesis. J Biol Chem. 2009 Jan 9;284(2):799-806. doi: 10.1074/jbc.M807546200. Epub 2008, Nov 9. PMID:19001381 doi:10.1074/jbc.M807546200
- ↑ Mohammed F, Cobbold M, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Engelhard VH, Willcox BE. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nat Immunol. 2008 Nov;9(11):1236-43. Epub 2008 Oct 5. PMID:18836451 doi:10.1038/ni.1660
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