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Dive into the research topics where Harvey T. McMahon is active.

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Featured researches published by Harvey T. McMahon.


Annual Review of Biochemistry | 2009

Mechanisms of Endocytosis

Gary J. Doherty; Harvey T. McMahon

Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes.


Nature | 2005

Membrane curvature and mechanisms of dynamic cell membrane remodelling

Harvey T. McMahon; Jennifer L. Gallop

Membrane curvature is no longer seen as a passive consequence of cellular activity but an active means to create membrane domains and to organize centres for membrane trafficking. Curvature can be dynamically modulated by changes in lipid composition, the oligomerization of curvature scaffolding proteins and the reversible insertion of protein regions that act like wedges in membranes. There is an interplay between curvature-generating and curvature-sensing proteins during vesicle budding. This is seen during vesicle budding and in the formation of microenvironments. On a larger scale, membrane curvature is a prime player in growth, division and movement.


Nature Reviews Molecular Cell Biology | 2004

The dynamin superfamily: universal membrane tubulation and fission molecules?

Gerrit J. K. Praefcke; Harvey T. McMahon

Dynamins are large GTPases that belong to a protein superfamily that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins. They are involved in many processes including budding of transport vesicles, division of organelles, cytokinesis and pathogen resistance. With sequenced genomes from Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, yeast species and Arabidopsis thaliana, we now have a complete picture of the members of the dynamin superfamily from different organisms. Here, we review the superfamily of dynamins and their related proteins, and propose that a common mechanism leading to membrane tubulation and/or fission could encompass their many varied functions.


Nature Reviews Molecular Cell Biology | 2011

Molecular mechanism and physiological functions of clathrin-mediated endocytosis

Harvey T. McMahon; Emmanuel Boucrot

Clathrin-mediated endocytosis is the endocytic portal into cells through which cargo is packaged into vesicles with the aid of a clathrin coat. It is fundamental to neurotransmission, signal transduction and the regulation of many plasma membrane activities and is thus essential to higher eukaryotic life. Morphological stages of vesicle formation are mirrored by progression through various protein modules (complexes). The process involves the formation of a putative FCH domain only (FCHO) initiation complex, which matures through adaptor protein 2 (AP2)-dependent cargo selection, and subsequent coat building, dynamin-mediated scission and finally auxilin- and heat shock cognate 70 (HSC70)-dependent uncoating. Some modules can be used in other pathways, and additions or substitutions confer cell specificity and adaptability.


Nature | 2002

Curvature of clathrin-coated pits driven by epsin

Marijn G. J. Ford; Ian G. Mills; Brian J. Peter; Yvonne Vallis; Gerrit J. K. Praefcke; Philip R. Evans; Harvey T. McMahon

Clathrin-mediated endocytosis involves cargo selection and membrane budding into vesicles with the aid of a protein coat. Formation of invaginated pits on the plasma membrane and subsequent budding of vesicles is an energetically demanding process that involves the cooperation of clathrin with many different proteins. Here we investigate the role of the brain-enriched protein epsin 1 in this process. Epsin is targeted to areas of endocytosis by binding the membrane lipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). We show here that epsin 1 directly modifies membrane curvature on binding to PtdIns(4,5)P2 in conjunction with clathrin polymerization. We have discovered that formation of an amphipathic α-helix in epsin is coupled to PtdIns(4,5)P2 binding. Mutation of residues on the hydrophobic region of this helix abolishes the ability to curve membranes. We propose that this helix is inserted into one leaflet of the lipid bilayer, inducing curvature. On lipid monolayers epsin alone is sufficient to facilitate the formation of clathrin-coated invaginations.


The EMBO Journal | 1994

Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly.

Tetsuya Hayashi; Harvey T. McMahon; S. Yamasaki; Thomas Binz; Yutaka Hata; Thomas C. Südhof; Heiner Niemann

Clostridial neurotoxins inhibit neurotransmitter release by selective and specific intracellular proteolysis of synaptobrevin/VAMP, synaptosomal‐associated protein of 25 kDa (SNAP‐25) or syntaxin. Here we show that in binary reactions synaptobrevin binds weakly to both SNAP‐25 and syntaxin, and SNAP‐25 binds to syntaxin. In the presence of all three components, a dramatic increase in the interaction strengths occurs and a stable sodium dodecyl sulfate‐resistant complex forms. Mapping of the interacting sequences reveals that complex formation correlates with the presence of predicted alpha‐helical structures, suggesting that membrane fusion involves intermolecular interactions via coiled‐coil structures. Most toxins only attack the free, and not the complexed, proteins, and proteolysis of the proteins by different clostridial neurotoxins has distinct inhibitory effects on the formation of synaptobrevin‐syntaxin‐SNAP‐25 complexes. Our data suggest that synaptobrevin, syntaxin and SNAP‐25 associate into a unique stable complex that functions in synaptic vesicle exocytosis.


Nature Reviews Molecular Cell Biology | 2008

Mechanisms of membrane fusion: disparate players and common principles

Sascha Martens; Harvey T. McMahon

Membrane fusion can occur between cells, between different intracellular compartments, between intracellular compartments and the plasma membrane and between lipid-bound structures such as viral particles and cellular membranes. In order for membranes to fuse they must first be brought together. The more highly curved a membrane is, the more fusogenic it becomes. We discuss how proteins, including SNAREs, synaptotagmins and viral fusion proteins, might mediate close membrane apposition and induction of membrane curvature to drive diverse fusion processes. We also highlight common principles that can be derived from the analysis of the role of these proteins.


Cell | 1995

COMPLEXINS : CYTOSOLIC PROTEINS THAT REGULATE SNAP RECEPTOR FUNCTION

Harvey T. McMahon; Markus Missler; Cai Li; Thomas C. Südhof

A family of proteins called complexins was discovered that compete with alpha-SNAP, but not synaptotagmin, for SNAP receptor binding. Complexins I and II are highly homologous hydrophilic proteins that are tightly conserved, with 100% identity among mouse, rat, and human complexin II. They are enriched in neurons where they colocalize with syntaxin and SNAP-25; in addition, complexin II is expressed ubiquitously at low levels. Complexins bind weakly to syntaxin alone and not at all to synaptobrevin and SNAP-25, but strongly to the SNAP receptor-core complex composed of these three molecules. They compete with alpha-SNAP for binding to the core complex but not with other interacting molecules, including synaptotagmin I, suggesting that the complexins regulate the sequential interactions of alpha-SNAP and synaptotagmins with the SNAP receptor during exocytosis.


The EMBO Journal | 2006

Mechanism of endophilin N-BAR domain-mediated membrane curvature.

Jennifer L. Gallop; Christine C. Jao; Helen M. Kent; P. Jonathan G. Butler; Philip R. Evans; Ralf Langen; Harvey T. McMahon

Endophilin‐A1 is a BAR domain‐containing protein enriched at synapses and is implicated in synaptic vesicle endocytosis. It binds to dynamin and synaptojanin via a C‐terminal SH3 domain. We examine the mechanism by which the BAR domain and an N‐terminal amphipathic helix, which folds upon membrane binding, work as a functional unit (the N‐BAR domain) to promote dimerisation and membrane curvature generation. By electron paramagnetic resonance spectroscopy, we show that this amphipathic helix is peripherally bound in the plane of the membrane, with the midpoint of insertion aligned with the phosphate level of headgroups. This places the helix in an optimal position to effect membrane curvature generation. We solved the crystal structure of rat endophilin‐A1 BAR domain and examined a distinctive insert protruding from the membrane interaction face. This insert is predicted to form an additional amphipathic helix and is important for curvature generation. Its presence defines an endophilin/nadrin subclass of BAR domains. We propose that N‐BAR domains function as low‐affinity dimers regulating binding partner recruitment to areas of high membrane curvature.


Science | 2007

How synaptotagmin promotes membrane fusion

Sascha Martens; Michael M. Kozlov; Harvey T. McMahon

Synaptic vesicles loaded with neurotransmitters are exocytosed in a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE)–dependent manner after presynaptic depolarization induces calcium ion (Ca2+) influx. The Ca2+ sensor required for fast fusion is synaptotagmin-1. The activation energy of bilayer-bilayer fusion is very high (≈40 kBT). We found that, in response to Ca2+ binding, synaptotagmin-1 could promote SNARE-mediated fusion by lowering this activation barrier by inducing high positive curvature in target membranes on C2-domain membrane insertion. Thus, synaptotagmin-1 triggers the fusion of docked vesicles by local Ca2+-dependent buckling of the plasma membrane together with the zippering of SNAREs. This mechanism may be widely used in membrane fusion.

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Yvonne Vallis

Laboratory of Molecular Biology

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David G. Nicholls

Buck Institute for Research on Aging

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Philip R. Evans

Laboratory of Molecular Biology

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Ian G. Mills

Queen's University Belfast

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Gary J. Doherty

Laboratory of Molecular Biology

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Marijn G. J. Ford

Laboratory of Molecular Biology

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Brian J. Peter

University of California

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