4CCA

Structure of human Munc18-2

Summary for 4CCA

• Entry DOI: 10.2210/pdb4cca/pdb
• Descriptor: SYNTAXIN-BINDING PROTEIN 2, CHLORIDE ION (3 entities in total)
• Functional Keywords: protein transport
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 67096.51

Authors

Hackmann, Y.,Graham, S.C.,Ehl, S.,Hoening, S.,Lehmberg, K.,Arico, M.,Owen, D.J.,Griffiths, G.G. (deposition date: 2013-10-21, release date: 2013-10-30, Last modification date: 2023-12-20)

Primary citation

Hackmann, Y.,Graham, S.C.,Ehl, S.,Hoening, S.,Lehmberg, K.,Arico, M.,Owen, D.J.,Griffiths, G.G.
Syntaxin Binding Mechanism and Disease-Causing Mutations in Munc18-2
Proc.Natl.Acad.Sci.USA, 110:E4482-, 2013

PubMed Abstract: 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 Å 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 ~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.

PubMed: 24194549
DOI: 10.1073/PNAS.1313474110

Experimental method

X-RAY DIFFRACTION (2.6 Å)