Membrane fusion

Department of Biochemistry, Dartmouth Medical School, 7200 Vail Building, Hanover, New Hampshire 03755-3844, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 08/2008; 15(7):658-64. DOI: 10.1038/nsmb.1451
Source: PubMed


Subcellular compartmentalization, cell growth, hormone secretion and neurotransmission require rapid, targeted, and regulated membrane fusion. Fusion entails extensive lipid rearrangements by two apposed (docked) membrane vesicles, joining their membrane proteins and lipids and mixing their luminal contents without lysis. Fusion of membranes in the secretory pathway involves Rab GTPases; their bound 'effector' proteins, which mediate downstream steps; SNARE proteins, which can 'snare' each other, in cis (bound to one membrane) or in trans (anchored to apposed membranes); and SNARE-associated proteins (SM proteins; NSF or Sec18p; SNAP or Sec17p; and others) cooperating with specific lipids to catalyze fusion. In contrast, mitochondrial and cell-cell fusion events are regulated by and use distinct catalysts.

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    • "); minimum number of peptide fragments ≥ 2, protein threshold: 99%, peptide threshold: 99%) therefore were interpreted as recruited upon Ca 2+ influx (Fig 5C 1 , Supplementary Table S3), and chiefly included proteins implicated in: (i) vesicle formation, fusion and traffic; (ii) enzymatic reactions; (iii) signaling ; and (iv) cytoskeletal dynamics and axonal transport (Fig 5C 1 ) (Sudhof, 2004; Schluter et al, 2006; Wickner & Schekman, 2008). We also uncovered interactions with other Ca 2+ -binding proteins, glutamate decarboxylase and vesicular GABA transporter (Fig 5C 1 ), reinforcing our transcriptome analysis. "
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    ABSTRACT: A hierarchical hormonal cascade along the hypothalamic-pituitary-adrenal axis orchestrates bodily responses to stress. Although corticotropin-releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single-cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH-releasing neuron population reliant on secretagogin's Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogin's loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.
    The EMBO Journal 11/2014; 34(1). DOI:10.15252/embj.201488977 · 10.43 Impact Factor
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    • "In any case, retromer-associated endosomes appear to be remarkably resistant to full fusion with the dendritic plasma membrane. Multiple mechanisms are already known to confer specificity on compartmental fusion (Wickner and Schekman, 2008) and we speculate that retromer, perhaps through its associated Bin-amphiphysin-Rvs (BAR) domain proteins that bind to and enforce curvature on endosome membranes (Bonifacino and Hurley, 2008), could confer additional specificity at the subcompartment level by imposing a physical barrier to full endosome fusion. Thus, retromer may function not only to positively select endosome cargoes for rapid surface delivery through recognition by a linked sorting protein such as SNX27, but also to negatively select other endosome-localized cargos that do not engage retromer by preventing full endosome fusion. "
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    ABSTRACT: A fundamental and still largely unresolved question is how neurons achieve rapid delivery of selected signaling receptors throughout the elaborate dendritic arbor. Here we show that this requires a conserved sorting machinery called retromer. Retromer-associated endosomes are distributed within dendrites in ∼2 μm intervals and supply frequent membrane fusion events into the dendritic shaft domain immediately adjacent to (<300 nm from) the donor endosome and typically without full endosome discharge. Retromer-associated endosomes contain β-adrenergic receptors as well as ionotropic glutamate receptors, and retromer knockdown reduces extrasynaptic insertion of adrenergic receptors as well as functional expression of AMPA and NMDA receptors at synapses. We propose that retromer supports a broadly distributed network of plasma membrane delivery to dendrites, organized in micron-scale axial territories to render essentially all regions of the postsynaptic surface within rapid diffusion distance of a local exocytic event.
    Neuron 04/2014; 82(1):55-62. DOI:10.1016/j.neuron.2014.02.018 · 15.05 Impact Factor
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    • "Membrane fusion is a fundamental process for protein/lipid trafficking, hormone secretion, and organelle morphogenesis in eukaryotic endomembrane systems. Fusion is catalyzed and tightly regulated by numerous conserved protein families123456: SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors)7, SNARE chaperones such as Sec1/Munc18-family (SM) proteins589, Rab GTPases, Rab effectors, and tethering complexes41011. Specific lipids, including sterols, diacylglycerol, phosphatidic acid (PA), phosphoinositides, and phosphatidylethanolamine (PE), are also required for efficient fusion of physiological membranes and cooperate with those essential protein components to form a fusion-competent membrane microdomain4121314151617. "
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    ABSTRACT: Trans-QabcR-SNARE pairing on opposing membranes is crucial for eukaryotic membrane fusion, but how selective pairs of Qabc- and R-SNARE proteins regulate membrane fusion specificity remains elusive. Here, we studied 14 purified full-length SNAREs that function in yeast endoplasmic reticulum (ER)-Golgi, intra-Golgi, endosomal, and vacuolar transport by comprehensively testing cis-QabcR-SNARE assembly and fusogenicity of reconstituted SNARE proteoliposomes. Strikingly, the cognate ER-Golgi and intra-Golgi SNARE-complex assemblies were highly stringent, whereas endosomal and vacuolar SNAREs assembled rather promiscuously into the non-cognate mixed complexes. However, these patterns of cis-SNARE assemblies cannot solely explain their potency to be fusogenic via trans-SNARE pairing: Only the vacuolar 3Q-SNARE combination is fusogenic in the absence of additional components; endosomal SNARE-dependent fusogenicity requires membrane-tethering factors; and ER-Golgi SNAREs can be fusogenic by synergistic actions of tethering factors and the cognate Sec1/Munc18-family protein Sly1p. Thus, our findings uncover multiple and distinct strategies of SNAREs to directly mediate fusion specificity.
    Scientific Reports 03/2014; 4:4277. DOI:10.1038/srep04277 · 5.58 Impact Factor
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