4z78: Difference between revisions

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==Weak TCR binding to an unstable insulin epitope drives type 1 diabetes==
==Weak TCR binding to an unstable insulin epitope drives type 1 diabetes==
<StructureSection load='4z78' size='340' side='right' caption='[[4z78]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='4z78' size='340' side='right'caption='[[4z78]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4z78]] is a 9 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z78 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z78 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4z78]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z78 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z78 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.304&#8491;</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=4z78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z78 OCA], [http://pdbe.org/4z78 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z78 RCSB], [http://www.ebi.ac.uk/pdbsum/4z78 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4z78 ProSAT]</span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4z78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z78 OCA], [https://pdbe.org/4z78 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z78 RCSB], [https://www.ebi.ac.uk/pdbsum/4z78 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z78 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:[http://omim.org/entry/176730 176730]].<ref>PMID:3470784</ref> <ref>PMID:2196279</ref> <ref>PMID:4019786</ref> <ref>PMID:1601997</ref>  Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:[http://omim.org/entry/125852 125852]]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:18192540</ref>  Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:[http://omim.org/entry/606176 606176]]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.<ref>PMID:17855560</ref> <ref>PMID:18162506</ref>  Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:[http://omim.org/entry/613370 613370]]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:18192540</ref> <ref>PMID:18162506</ref> <ref>PMID:20226046</ref>  [[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[http://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 ==
== Function ==
[[http://www.uniprot.org/uniprot/HA1D_MOUSE HA1D_MOUSE]] Involved in the presentation of foreign antigens to the immune system. [[http://www.uniprot.org/uniprot/INS_HUMAN INS_HUMAN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver. [[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.  
[https://www.uniprot.org/uniprot/HA1D_MOUSE HA1D_MOUSE] Involved in the presentation of foreign antigens to the immune system.
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Beta-2 microglobulin|Beta-2 microglobulin]]
*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Cole, D K]]
[[Category: Homo sapiens]]
[[Category: Rizkallah, P J]]
[[Category: Large Structures]]
[[Category: H-2kd]]
[[Category: Mus musculus]]
[[Category: Immune system]]
[[Category: Cole DK]]
[[Category: Immunoglobulin]]
[[Category: Rizkallah PJ]]
[[Category: Type 1 diabetes]]

Latest revision as of 09:58, 17 October 2024

Weak TCR binding to an unstable insulin epitope drives type 1 diabetesWeak TCR binding to an unstable insulin epitope drives type 1 diabetes

Structural highlights

4z78 is a 9 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.304Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HA1D_MOUSE Involved in the presentation of foreign antigens to the immune system.

Publication Abstract from PubMed

The NOD mouse model of type 1 diabetes (T1D) continues to be an important tool for delineating the role of T-cell-mediated destruction of pancreatic beta-cells. However, little is known about the molecular mechanisms that enable this disease pathway. We show that insulin reactivity by a CD8+ T-cell clone known to induce T1D is characterised by weak T cell antigen receptor (TCR) binding to a relatively unstable peptide-major histocompatibility complex (pMHC). The structure of the native 9-mer and 10-mer insulin epitopes demonstrated that peptide residues 7 and 8 form a prominent solvent exposed bulge that could potentially be the main focus of TCR binding. The C-terminus of the peptide governed pMHC stability. Unexpectedly, we further demonstrate a novel mode of flexible peptide presentation in which the MHC peptide-binding groove is able to 'open the back door' to accommodate extra C-terminal peptide residues.

Distortion of the MHC class I binding groove to accommodate an insulin-derived 10-mer peptide.,Motozono C, Pearson JA, De Leenheer E, Rizkallah PJ, Beck K, Trimby A, Sewell AK, Wong FS, Cole DK J Biol Chem. 2015 Jun 17. pii: jbc.M114.622522. PMID:26085090[1]

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

See Also

References

  1. ↑ Motozono C, Pearson JA, De Leenheer E, Rizkallah PJ, Beck K, Trimby A, Sewell AK, Wong FS, Cole DK. Distortion of the MHC class I binding groove to accommodate an insulin-derived 10-mer peptide. J Biol Chem. 2015 Jun 17. pii: jbc.M114.622522. PMID:26085090 doi:http://dx.doi.org/10.1074/jbc.M114.622522

4z78, resolution 2.30Å

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