4cca: Difference between revisions
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== | ==Structure of human Munc18-2== | ||
[[http://www.uniprot.org/uniprot/STXB2_HUMAN STXB2_HUMAN | <StructureSection load='4cca' size='340' side='right'caption='[[4cca]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cca]] 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=4CCA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CCA 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]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=4cca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cca OCA], [https://pdbe.org/4cca PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cca RCSB], [https://www.ebi.ac.uk/pdbsum/4cca PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cca ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/STXB2_HUMAN STXB2_HUMAN] Familial hemophagocytic lymphohistiocytosis. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/STXB2_HUMAN STXB2_HUMAN] Involved in intracellular vesicle trafficking and vesicle fusion with membranes. Contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate membrane fusion. Regulates cytotoxic granule exocytosis in natural killer (NK) cells.<ref>PMID:19804848</ref> <ref>PMID:19884660</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mutations in either syntaxin 11 (Stx11) or Munc18-2 abolish cytotoxic T lymphocytes (CTL) and natural killer cell (NK) cytotoxicity, and give rise to familial hemophagocytic lymphohistiocytosis (FHL4 or FHL5, respectively). Although Munc18-2 is known to interact with Stx11, little is known about the molecular mechanisms governing the specificity of this interaction or how in vitro IL-2 activation leads to compensation of CTL and NK cytotoxicity. To understand how mutations in Munc18-2 give rise to disease, we have solved the structure of human Munc18-2 at 2.6 A resolution and mapped 18 point mutations. The four surface mutations identified (R39P, L130S, E132A, P334L) map exclusively to the predicted syntaxin and soluble N-ethylmaleimide-sensitive factor accessory protein receptor binding sites of Munc18-2. We find that Munc18-2 binds the N-terminal peptide of Stx11 with a approximately 20-fold higher affinity than Stx3, suggesting a potential role in selective binding. Upon IL-2 activation, levels of Stx3 are increased, favoring Munc18-2 binding when Stx11 is absent. Similarly, Munc18-1, expressed in IL-2-activated CTL, is capable of binding Stx11. These findings provide potential explanations for restoration of Munc18-Stx function and cytotoxicity in IL-2-activated cells. | |||
Syntaxin binding mechanism and disease-causing mutations in Munc18-2.,Hackmann Y, Graham SC, Ehl S, Honing S, Lehmberg K, Arico M, Owen DJ, Griffiths GM Proc Natl Acad Sci U S A. 2013 Nov 5. PMID:24194549<ref>PMID:24194549</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4cca" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Syntaxin-binding protein|Syntaxin-binding protein]] | |||
[[Category: | == References == | ||
[[Category: Arico | <references/> | ||
[[Category: Ehl | __TOC__ | ||
[[Category: Graham | </StructureSection> | ||
[[Category: Griffiths | [[Category: Homo sapiens]] | ||
[[Category: Hackmann | [[Category: Large Structures]] | ||
[[Category: Hoening | [[Category: Arico M]] | ||
[[Category: Lehmberg | [[Category: Ehl S]] | ||
[[Category: Owen | [[Category: Graham SC]] | ||
[[Category: Griffiths GG]] | |||
[[Category: Hackmann Y]] | |||
[[Category: Hoening S]] | |||
[[Category: Lehmberg K]] | |||
[[Category: Owen DJ]] | |||
Latest revision as of 15:07, 20 December 2023
Structure of human Munc18-2Structure of human Munc18-2
Structural highlights
DiseaseSTXB2_HUMAN Familial hemophagocytic lymphohistiocytosis. The disease is caused by mutations affecting the gene represented in this entry. FunctionSTXB2_HUMAN Involved in intracellular vesicle trafficking and vesicle fusion with membranes. Contributes to the granule exocytosis machinery through interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that regulate membrane fusion. Regulates cytotoxic granule exocytosis in natural killer (NK) cells.[1] [2] Publication Abstract from PubMedMutations in either syntaxin 11 (Stx11) or Munc18-2 abolish cytotoxic T lymphocytes (CTL) and natural killer cell (NK) cytotoxicity, and give rise to familial hemophagocytic lymphohistiocytosis (FHL4 or FHL5, respectively). Although Munc18-2 is known to interact with Stx11, little is known about the molecular mechanisms governing the specificity of this interaction or how in vitro IL-2 activation leads to compensation of CTL and NK cytotoxicity. To understand how mutations in Munc18-2 give rise to disease, we have solved the structure of human Munc18-2 at 2.6 A resolution and mapped 18 point mutations. The four surface mutations identified (R39P, L130S, E132A, P334L) map exclusively to the predicted syntaxin and soluble N-ethylmaleimide-sensitive factor accessory protein receptor binding sites of Munc18-2. We find that Munc18-2 binds the N-terminal peptide of Stx11 with a approximately 20-fold higher affinity than Stx3, suggesting a potential role in selective binding. Upon IL-2 activation, levels of Stx3 are increased, favoring Munc18-2 binding when Stx11 is absent. Similarly, Munc18-1, expressed in IL-2-activated CTL, is capable of binding Stx11. These findings provide potential explanations for restoration of Munc18-Stx function and cytotoxicity in IL-2-activated cells. Syntaxin binding mechanism and disease-causing mutations in Munc18-2.,Hackmann Y, Graham SC, Ehl S, Honing S, Lehmberg K, Arico M, Owen DJ, Griffiths GM Proc Natl Acad Sci U S A. 2013 Nov 5. PMID:24194549[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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