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Syntaxin binding mechanism and disease-causing mutations in Munc18-2

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Syntaxin binding mechanism and disease-causing mutations in Munc18-2. / Hackmann, Yvonne; Graham, Stephen C; Ehl, Stephan; Höning, Stefan; Lehmberg, Kai; Aricò, Maurizio; Owen, David J; Griffiths, Gillian M.

In: P NATL ACAD SCI USA, Vol. 110, No. 47, 19.11.2013, p. E4482-91.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hackmann, Y, Graham, SC, Ehl, S, Höning, S, Lehmberg, K, Aricò, M, Owen, DJ & Griffiths, GM 2013, 'Syntaxin binding mechanism and disease-causing mutations in Munc18-2', P NATL ACAD SCI USA, vol. 110, no. 47, pp. E4482-91. https://doi.org/10.1073/pnas.1313474110

APA

Hackmann, Y., Graham, S. C., Ehl, S., Höning, S., Lehmberg, K., Aricò, M., Owen, D. J., & Griffiths, G. M. (2013). Syntaxin binding mechanism and disease-causing mutations in Munc18-2. P NATL ACAD SCI USA, 110(47), E4482-91. https://doi.org/10.1073/pnas.1313474110

Vancouver

Hackmann Y, Graham SC, Ehl S, Höning S, Lehmberg K, Aricò M et al. Syntaxin binding mechanism and disease-causing mutations in Munc18-2. P NATL ACAD SCI USA. 2013 Nov 19;110(47):E4482-91. https://doi.org/10.1073/pnas.1313474110

Bibtex

@article{05fc4a5afdbb405eaed8fc95b3355838,
title = "Syntaxin binding mechanism and disease-causing mutations in Munc18-2",
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 {\AA} 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.",
keywords = "Animals, Blotting, Western, Crystallization, Evolution, Molecular, HEK293 Cells, Humans, Immunohistochemistry, Killer Cells, Natural, Lymphohistiocytosis, Hemophagocytic, Models, Molecular, Munc18 Proteins, Point Mutation, Protein Binding, Qa-SNARE Proteins, Sf9 Cells, Spodoptera, T-Lymphocytes, Cytotoxic",
author = "Yvonne Hackmann and Graham, {Stephen C} and Stephan Ehl and Stefan H{\"o}ning and Kai Lehmberg and Maurizio Aric{\`o} and Owen, {David J} and Griffiths, {Gillian M}",
year = "2013",
month = nov,
day = "19",
doi = "10.1073/pnas.1313474110",
language = "English",
volume = "110",
pages = "E4482--91",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "47",

}

RIS

TY - JOUR

T1 - Syntaxin binding mechanism and disease-causing mutations in Munc18-2

AU - Hackmann, Yvonne

AU - Graham, Stephen C

AU - Ehl, Stephan

AU - Höning, Stefan

AU - Lehmberg, Kai

AU - Aricò, Maurizio

AU - Owen, David J

AU - Griffiths, Gillian M

PY - 2013/11/19

Y1 - 2013/11/19

N2 - 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.

AB - 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.

KW - Animals

KW - Blotting, Western

KW - Crystallization

KW - Evolution, Molecular

KW - HEK293 Cells

KW - Humans

KW - Immunohistochemistry

KW - Killer Cells, Natural

KW - Lymphohistiocytosis, Hemophagocytic

KW - Models, Molecular

KW - Munc18 Proteins

KW - Point Mutation

KW - Protein Binding

KW - Qa-SNARE Proteins

KW - Sf9 Cells

KW - Spodoptera

KW - T-Lymphocytes, Cytotoxic

U2 - 10.1073/pnas.1313474110

DO - 10.1073/pnas.1313474110

M3 - SCORING: Journal article

C2 - 24194549

VL - 110

SP - E4482-91

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 47

ER -