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==Crystal structure of the D76H Beta-2 Microglobulin mutant==
==Crystal structure of the D76H Beta-2 Microglobulin mutant==
<StructureSection load='4rmv' size='340' side='right' caption='[[4rmv]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
<StructureSection load='4rmv' size='340' side='right' caption='[[4rmv]], [[Resolution|resolution]] 1.46&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4rmv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RMV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RMV FirstGlance]. <br>
<table><tr><td colspan='2'>[[4rmv]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RMV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RMV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yxf|2yxf]], [[4fxl|4fxl]], [[4rmq|4rmq]], [[4rmr|4rmr]], [[4rms|4rms]], [[4rmt|4rmt]], [[4rmu|4rmu]], [[4rmw|4rmw]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yxf|2yxf]], [[4fxl|4fxl]], [[4rmq|4rmq]], [[4rmr|4rmr]], [[4rms|4rms]], [[4rmt|4rmt]], [[4rmu|4rmu]], [[4rmw|4rmw]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rmv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rmv OCA], [http://pdbe.org/4rmv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rmv RCSB], [http://www.ebi.ac.uk/pdbsum/4rmv PDBsum]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">B2M, CDABP0092, HDCMA22P, NM_004048 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rmv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rmv OCA], [http://pdbe.org/4rmv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rmv RCSB], [http://www.ebi.ac.uk/pdbsum/4rmv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rmv ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
Line 11: Line 13:
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.  
[[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (beta2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of beta2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline beta2m. The destabilization of the outer strands of D76N beta2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.
Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity.,Le Marchand T, de Rosa M, Salvi N, Sala BM, Andreas LB, Barbet-Massin E, Sormanni P, Barbiroli A, Porcari R, Sousa Mota C, de Sanctis D, Bolognesi M, Emsley L, Bellotti V, Blackledge M, Camilloni C, Pintacuda G, Ricagno S Nat Commun. 2018 Apr 25;9(1):1658. doi: 10.1038/s41467-018-04078-y. PMID:29695721<ref>PMID:29695721</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4rmv" style="background-color:#fffaf0;"></div>
==See Also==
*[[Beta-2 microglobulin|Beta-2 microglobulin]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Bolognesi, M]]
[[Category: Bolognesi, M]]
[[Category: Ricagno, S]]
[[Category: Ricagno, S]]

Revision as of 08:46, 27 June 2018

Crystal structure of the D76H Beta-2 Microglobulin mutantCrystal structure of the D76H Beta-2 Microglobulin mutant

Structural highlights

4rmv is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:B2M, CDABP0092, HDCMA22P, NM_004048 (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

[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

Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (beta2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of beta2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline beta2m. The destabilization of the outer strands of D76N beta2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.

Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity.,Le Marchand T, de Rosa M, Salvi N, Sala BM, Andreas LB, Barbet-Massin E, Sormanni P, Barbiroli A, Porcari R, Sousa Mota C, de Sanctis D, Bolognesi M, Emsley L, Bellotti V, Blackledge M, Camilloni C, Pintacuda G, Ricagno S Nat Commun. 2018 Apr 25;9(1):1658. doi: 10.1038/s41467-018-04078-y. PMID:29695721[15]

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

See Also

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. ↑ Le Marchand T, de Rosa M, Salvi N, Sala BM, Andreas LB, Barbet-Massin E, Sormanni P, Barbiroli A, Porcari R, Sousa Mota C, de Sanctis D, Bolognesi M, Emsley L, Bellotti V, Blackledge M, Camilloni C, Pintacuda G, Ricagno S. Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity. Nat Commun. 2018 Apr 25;9(1):1658. doi: 10.1038/s41467-018-04078-y. PMID:29695721 doi:http://dx.doi.org/10.1038/s41467-018-04078-y

4rmv, resolution 1.46Å

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