scholarly journals Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion

Blood ◽  
2015 ◽  
Vol 125 (10) ◽  
pp. 1566-1577 ◽  
Author(s):  
Waldo A. Spessott ◽  
Maria L. Sanmillan ◽  
Margaret E. McCormick ◽  
Nishant Patel ◽  
Joyce Villanueva ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Dominant Negative ◽  
Snare Complex ◽  
Complex Assembly ◽  
Mutant Proteins ◽  
Key Points ◽  
Lymphocyte Cytotoxicity ◽  
Dominant Negative Mutations

Key Points Monoallelic STXBP2 mutations affecting codon 65 impair lymphocyte cytotoxicity and contribute to hemophagocytic lymphohistiocytosis. Munc18-2R65Q/W mutant proteins function in a dominant-negative manner to impair membrane fusion and arrest SNARE-complex assembly.

Mutagenesis of Ste18, a putative Gγ subunit in the Saccharomyces cerevisiae pheromone response pathway

1992 ◽  
Vol 70 (10-11) ◽  
pp. 1230-1237 ◽  
Author(s):  
Malcolm Whiteway ◽  
Daniel Dignard ◽  
David Y. Thomas
Keyword(s):  
Signal Transduction ◽  
Dominant Negative ◽  
Saturation Mutagenesis ◽  
Pheromone Response ◽  
Mutant Proteins ◽  
Pheromone Response Pathway ◽  
Allele Specific ◽  
Dominant Negative Mutations ◽  
Compensatory Mutations ◽  
Mutant Genes

The yeast STE18 gene product has sequence and functional similarity to the γ subunits of G proteins. The cloned STE18 gene was subjected to a saturation mutagenesis using doped oligonucleotides. The populations of mutant genes were screened for two classes of STE18 mutations, those that allowed for increased mating of a strain containing a defective STE4 gene (compensators) and those that inhibited mating even in the presence of a functional STE18 gene (dominant negatives). Three amino acid substitutions that enhanced mating in a specific STE4 (Gβ) point mutant background were identified. These compensatory mutations were allele specific and had no detectable phenotype of their own; they may define residues that mediate an association between the Gβ and Gγ subunits or in the association of the Gβγ subunit with other components of the signalling pathway. Several dominant negative mutations were also identified, including two C terminal truncations. These mutant proteins were unable to function in signal transduction by themselves, but they prevented signal transduction mediated by pheromone, as well as the constitutive signalling which is present in cells defective in the GPAI (Gα) gene. These mutant proteins may sequester Gβ or some other component of the signalling machinery in a nonfunctional complex. Key wordsi yeast, G protein, STE18, mutagenesis, pheromone response.

scholarly journals Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis

Blood ◽  
2014 ◽  
Vol 124 (8) ◽  
pp. 1331-1334 ◽  
Author(s):  
Kejian Zhang ◽  
Shanmuganathan Chandrakasan ◽  
Heather Chapman ◽  
C. Alexander Valencia ◽  
Ammar Husami ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Synergistic Effects ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Key Points ◽  
Lymphocyte Cytotoxicity

Key Points Synergistic effects were observed in the granule mediated lymphocyte cytotoxicity. Digenic pathogenesis contributed to the development of hemophagocytic lymphohistiocytosis.

scholarly journals Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ewa Sitarska ◽  
Junjie Xu ◽  
Seungmee Park ◽  
Xiaoxia Liu ◽  
Bradley Quade ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Membrane Fusion ◽  
Neurotransmitter Release ◽  
Specific Binding ◽  
Snare Complex ◽  
Gain Of Function ◽  
Complex Assembly ◽  
Data Support

Munc18-1 orchestrates SNARE complex assembly together with Munc13-1 to mediate neurotransmitter release. Munc18-1 binds to synaptobrevin, but the relevance of this interaction and its relation to Munc13 function are unclear. NMR experiments now show that Munc18-1 binds specifically and non-specifically to synaptobrevin. Specific binding is inhibited by a L348R mutation in Munc18-1 and enhanced by a D326K mutation designed to disrupt the ‘furled conformation’ of a Munc18-1 loop. Correspondingly, the activity of Munc18-1 in reconstitution assays that require Munc18-1 and Munc13-1 for membrane fusion is stimulated by the D326K mutation and inhibited by the L348R mutation. Moreover, the D326K mutation allows Munc13-1-independent fusion and leads to a gain-of-function in rescue experiments in Caenorhabditis elegans unc-18 nulls. Together with previous studies, our data support a model whereby Munc18-1 acts as a template for SNARE complex assembly, and autoinhibition of synaptobrevin binding contributes to enabling regulation of neurotransmitter release by Munc13-1.

Buforin-1 blocks neuronal SNARE-mediated membrane fusion by inhibiting SNARE complex assembly

2019 ◽  
Vol 514 (1) ◽  
pp. 105-111
Author(s):  
Jung Gi Lee ◽  
Young-Joon Ko ◽  
Ji-Hye Choi ◽  
Min Jeong Jo ◽  
Youngsoo Jun ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Snare Complex ◽  
Complex Assembly

scholarly journals Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Peng Yue ◽  
Yubo Zhang ◽  
Kunrong Mei ◽  
Shaoxiao Wang ◽  
Johannes Lesigang ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Snare Complex ◽  
Complex Assembly

scholarly journals Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Vivien Béziat ◽  
Simon J. Tavernier ◽  
Yin-Huai Chen ◽  
Cindy S. Ma ◽  
Marie Materna ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Mutant Proteins ◽  
Skeletal Abnormalities ◽  
Tyrosine Residues ◽  
Hyper Ige Syndrome ◽  
Dominant Negative Mutations ◽  
Allergic Manifestations ◽  
Stat3 Mutations

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

scholarly journals Asymmetric Rab activation of vacuolar HOPS to catalyze SNARE complex assembly

2020 ◽  
Vol 31 (10) ◽  
pp. 1060-1068
Author(s):  
Thomas Torng ◽  
Hongki Song ◽  
William Wickner
Keyword(s):  
Membrane Fusion ◽  
Fusion Proteins ◽  
Snare Complex ◽  
Rab Proteins ◽  
Complex Assembly ◽  
Yeast Vacuole ◽  
Vacuole Fusion

Rab proteins are known to recruit effector complexes for membrane fusion. Using pure yeast vacuole fusion proteins, we now show that the Rab Ypt7 and vacuolar lipids allosterically activate the effector HOPS to catalyze SNARE complex assembly when the R-SNARE is bound to the same membrane as Ypt7.

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