4cca | pdb_00004cca

Structure of human Munc18-2

spinqualitylabelsall models 4cca, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4cca 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: CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [STXB2_HUMAN] Familial hemophagocytic lymphohistiocytosis. The disease is caused by mutations affecting the gene represented in this entry. Function [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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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