| Structural highlights
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
[1B35_HUMAN] Involved in the presentation of foreign antigens to the immune system. [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
Given a limited set of TCR V genes which are used to create TCRs that are reactive to different ligands, such as MHC class I, MHC class II and MHC-like proteins (for example, MIC molecules and CD1 molecules), the Vdelta1 segment can be rearranged with Ddelta-Jdelta-Cdelta or Jalpha-Calpha segments, to form classical gammadeltaTCR or uncommon alphabetaTCR using a Vdelta1 segment (delta/alphabetaTCR). Here we have determined two complex structures of the delta/alphabetaTCRs (S19-2 and TU55) bound to different locus-disparate MHCIs with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble classical alphabetaTCRs, but display a strong tilt binding geometry of Vdelta1 domain towards the HLA alpha1 helix, due to a conserved extensive interaction between the CDR1delta loop and N-terminal region of alpha1 helix (mainly in position 62). The aromatic amino acids of the CDR1delta loop exploit different conformations ("aromatic-ladder" or "aromatic-hairpin") to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules, and thus, may potentially explain the nature of TCR cross-reactivity. In addition, the length of CDR3delta loop could affect the extent of tilt binding of Vdelta1 domain, and adaptively, the pairing Vbeta domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring the TCR specificity to a certain peptide-MHC. Our data have provided further structural insights into the TCR recognition of classical pMHCI molecules, unifying the cross-reactivity and specificity together.IMPORTANCE The specificity of alphabeta T cell recognition is determined by the CDR loops of the alphabetaTCR and the general binding mode of alphabetaTCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR alpha/delta chain locus, some Vdelta segments can rearrange with Calpha segment, forming a hybrid VdeltaCalphaVbetaCbeta TCR, delta/alphabetaTCR. However, the basis for the molecular recognition of such TCRs to their ligands is elusive. Here, an alphabetaTCR using Vdelta1 segment, S19-2, is isolated from a HIV-infected patient, in an HLA-A*24:02 restricted manner. Then we solved the crystal structures of S19-2 TCR and another delta/alphabetaTCR TU55 binding to their ligands respectively, revealing a conserved Vdelta1 binding feature. Further binding kinetics analysis reveals that the S19-2 and TU55 TCRs bind pHLA very tightly and long-lastingly. Our results illustrate the binding mode of a TCR using Vdelta1 segment to its ligand, virus-derived pHLA.
Conserved Vdelta1 binding geometry in a setting of locus-disparate pHLA recognition by delta/alphabetaTCRs: insight into recognition of HIV peptides by TCR.,Shi Y, Kawana-Tachikawa A, Gao F, Qi J, Liu C, Gao J, Cheng H, Ueno T, Iwamoto A, Gao GF J Virol. 2017 Jun 14. pii: JVI.00725-17. doi: 10.1128/JVI.00725-17. PMID:28615212[15]
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
- ↑ Shi Y, Kawana-Tachikawa A, Gao F, Qi J, Liu C, Gao J, Cheng H, Ueno T, Iwamoto A, Gao GF. Conserved Vdelta1 binding geometry in a setting of locus-disparate pHLA recognition by delta/alphabetaTCRs: insight into recognition of HIV peptides by TCR. J Virol. 2017 Jun 14. pii: JVI.00725-17. doi: 10.1128/JVI.00725-17. PMID:28615212 doi:http://dx.doi.org/10.1128/JVI.00725-17
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