Universität zu Köln

Hackmann, Yvonne, Graham, Stephen C., Ehl, Stephan ORCID: 0000-0002-9265-2721, Hoening, Stefan, Lehmberg, Kai, Arico, Maurizio ORCID: 0000-0002-1908-6671, Owen, David J. and Griffiths, Gillian M. (2013). Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc. Natl. Acad. Sci. U. S. A., 110 (47). S. E4482 - 10. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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 angstrom 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 similar to 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hackmann, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Graham, Stephen C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehl, Stephan UNSPECIFIED orcid.org/0000-0002-9265-2721 UNSPECIFIED Hoening, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmberg, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED Arico, Maurizio UNSPECIFIED orcid.org/0000-0002-1908-6671 UNSPECIFIED Owen, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Griffiths, Gillian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-471918
DOI:	10.1073/pnas.1313474110
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	110
Number:	47
Page Range:	S. E4482 - 10
Date:	2013
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language N-PEPTIDE; CLOSED-CONFORMATION; STRUCTURAL BASIS; DOMAIN 3A; SNARE; COMPLEX; PROTEIN; MEMBRANE; FUSION; ACTIVATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47191