View source for 7nmy


==Crystal structure of beta-2-microglobulin D76Y mutant==
<StructureSection load='7nmy' size='340' side='right'caption='[[7nmy]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7nmy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NMY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NMY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nmy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nmy OCA], [https://pdbe.org/7nmy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nmy RCSB], [https://www.ebi.ac.uk/pdbsum/7nmy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nmy ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[https://omim.org/entry/241600 241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.<ref>PMID:16549777</ref>   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.<ref>PMID:3532124</ref> <ref>PMID:1336137</ref> <ref>PMID:7554280</ref> <ref>PMID:4586824</ref> <ref>PMID:8084451</ref> <ref>PMID:12119416</ref> <ref>PMID:12796775</ref> <ref>PMID:16901902</ref> <ref>PMID:16491088</ref> <ref>PMID:17646174</ref> <ref>PMID:18835253</ref> <ref>PMID:18395224</ref> <ref>PMID:19284997</ref> 
== Function ==
[https://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 ==
Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class of proteins assembles into amyloid fibrils remains poorly understood, principally because of the complex effects of amino acid substitutions on protein stability, solubility, and aggregation propensity. We address this question using beta2-microglobulin (beta2m) as a model system, focusing on D76N-beta2m that is involved in hereditary amyloidosis. This amino acid substitution causes the aggregation-resilient wild-type protein to become highly aggregation prone in vitro, although the mechanism by which this occurs remained elusive. Here, we identify the residues key to protecting beta2m from aggregation by coupling aggregation with antibiotic resistance in E. coli using a tripartite beta-lactamase assay (TPBLA). By performing saturation mutagenesis at three different sites (D53X-, D76X-, and D98X-beta2m) we show that residue 76 has a unique ability to drive beta2m aggregation in vivo and in vitro. Using a randomly mutated D76N-beta2m variant library, we show that all of the mutations found to improve protein behavior involve residues in a single aggregation-prone region (APR) (residues 60 to 66). Surprisingly, no correlation was found between protein stability and protein aggregation rate or yield, with several mutations in the APR decreasing aggregation without affecting stability. Together, the results demonstrate the power of the TPBLA to develop proteins that are resilient to aggregation and suggest a model for D76N-beta2m aggregation involving the formation of long-range couplings between the APR and Asn76 in a nonnative state.

The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis.,Guthertz N, van der Kant R, Martinez RM, Xu Y, Trinh CH, Iorga BI, Rousseau F, Schymkowitz J, Brockwell DJ, Radford SE Proc Natl Acad Sci U S A. 2022 May 31;119(22):e2200468119. doi: , 10.1073/pnas.2200468119. Epub 2022 May 25. PMID:35613051<ref>PMID:35613051</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7nmy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Guthertz N]]