抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

In neural systems, information is often carried by ensembles of cells rather than by individual units. Optical indicators provide a powerful means to reveal such distributed activity, particularly when protein-based and encodable in DNA: encodable probes can be introduced into cells, tissues, or transgenic organisms by genetic manipulation, selectively expressed in anatomically or functionally defined groups of cells, and, ideally, recorded in situ, without a requirement for exogenous cofactors. Here we describe sensors for secretion and neurotransmission that fulfil these criteria. We have developed pH-sensitive mutants of green fluorescent protein ('pHluorins') by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles to monitor vesicle exocytosis and recycling. When linked to a vesicle membrane protein, pHluorins were sorted to secretory and synaptic vesicles and reported transmission at individual synaptic boutons, as well as secretion and fusion pore 'flicker' of single secretory granules.

Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins

Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.

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SNAREs--engines for membrane fusion.

The evolutionarily conserved SNARE proteins and their complexes are involved in the fusion of vesicles with their target membranes; however, the overall organization and structural details of these complexes are unknown. Here we report the X-ray crystal structure at 2.4 A resolution of a core synaptic fusion complex containing syntaxin-1 A, synaptobrevin-II and SNAP-25B. The structure reveals a highly twisted and parallel four-helix bundle that differs from the bundles described for the haemagglutinin and HIV/SIV gp41 membrane-fusion proteins. Conserved leucine-zipper-like layers are found at the centre of the synaptic fusion complex. Embedded within these leucine-zipper layers is an ionic layer consisting of an arginine and three glutamine residues contributed from each of the four alpha-helices. These residues are highly conserved across the entire SNARE family. The regions flanking the leucine-zipper-like layers contain a hydrophobic core similar to that of more general four-helix-bundle proteins. The surface of the synaptic fusion complex is highly grooved and possesses distinct hydrophilic, hydrophobic and charged regions. These characteristics may be important for membrane fusion and for the binding of regulatory factors affecting neurotransmission.

Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution

SNAREpins: Minimal Machinery for Membrane Fusion

ng properties oftheantibodies weredetermined inaninvitro assay, based onthetoxin-mediated inhibition of norepinephrine release fromratbrain particles. Twomonoclonal antibodies recognizing epitopes within the regions Ser-744 toSer-864 andIle-1224 toAsp-1315 could neutralize thetoxin. A third nonneutralizing antibody wasshowntorecognize thesynthetic peptide Phe-947 toGlu-967 derived fromthetetanus toxin sequence. Thispeptide contains ahumanT-cell epitope. Tetanus toxin isahighly potent neurotoxin produced by theanaerobic bacterium Clostridium tetani. Thetoxin blocks release ofinhibitory transmitter substances from central synapses (21) after aprocess that involves binding to ganglioside receptors atthenervetermini, receptor-mediatedendocytosis, intra-axonal transport, andtranssynaptic

Expression ofTetanus ToxinSubfragments InVitro and Characterization ofEpitopes

Summary Synaptic vesicles loaded with neurotransmitters fuse with the plasma membrane to release their content into the extracellular space, thereby allowing neuronal communication. The membrane fusion process is mediated by a conserved set of SNARE proteins: vesicular synaptobrevin and plasma membrane syntaxin and SNAP-25. Recent data suggest that the fusion process may be subject to regulation by local lipid metabolism. Here, we have performed a screen of lipid compounds to identify positive regulators of vesicular synaptobrevin. We show that sphingosine, a releasable backbone of sphingolipids, activates synaptobrevin in synaptic vesicles to form the SNARE complex implicated in membrane fusion. Consistent with the role of synaptobrevin in vesicle fusion, sphingosine upregulated exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and hippocampal neurons, but not in neurons obtained from synaptobrevin-2 knockout mice. Further mechanistic insights suggest that sphingosine acts on the synaptobrevin/phospholipid interface, defining a novel function for this important lipid regulator.

Sphingosine Facilitates SNARE Complex Assembly and Activates

Die Erfindung betrifft ein Polypeptid bestehend aus einer Aminosauresequenz, die zu mindestens 70% identisch ist mit der Aminosauresequenz des synaptischen Vesikel Glykoproteins 2C aus Homo sapiens, und dass das Polypeptid das HC- Fragment von Botulinus Neurotoxin A bindet, mit der Masgabe, dass das Polypeptid nicht das synaptische Vesikel Glykoprotein 2C aus Homo sapiens ist.

Der botulinus neurotoxin a proteinrezeptor und seine anwendungen

Polypeptide consisting of an amino acid sequence which is identical to at least 70% with the amino acid sequence of the synaptic vesicle glycoprotein 2C of Homo sapiens, wherein the polypeptide of the H

Thomas Binz

Papers

Expression ofTetanus ToxinSubfragments InVitro and Characterization ofEpitopes

Sphingosine Facilitates SNARE Complex Assembly and Activates

Der botulinus neurotoxin a proteinrezeptor und seine anwendungen

The botulinum neurotoxin A receptor protein and its applications