Dr Harvey McMahon FRS University positionMRC Programme Leader Dr Harvey McMahon FRS is pleased to consider applications from prospective PhD students. InstitutesMedical Research Council Laboratory of Molecular Biology Home pagehttp://www.endocytosis.org/ (personal home page) Research ThemeInterestsMolecular mechanisms of vesicle exocytosis, endocytosis and membrane trafficking in neurons. We are interested in understanding basic mechanisms of vesicle trafficking, especially at the synapse, where synaptic vesicle exocytosis and endocytosis occur with high speed and fidelity. We have described many of the protein components involved in clathrin-mediated vesicle retrieval in the synapse. We are now describing other faster endocytic pathways that operate in parallel with the slower clathrin-mediated retrieval pathway. We have recently discovered how vesicle exocytosis is so finely tuned to calcium entry and this in turn points to similar basic underlying mechanisms of control that are likely to operate in all vesicle fusion events. We would like to further understand the control points for post synaptic vesicle trafficking and are currently investigating the function of oligophrenin, mutations in which give rise to mental retardation.  Depiction of a protein interaction network underlying nerve function Click image to view full-size Research Focus
EquipmentAnalytical ultracentrifugation Cell culture Confocal microscopy Electron paramagnetic resonance imaging Enzyme assays Fluorescence microscopy FPLC/HPLC Immunohistochemistry Isothermal titration calorimetry Microscopy Protein purification Recombinant protein expression X-ray crystallography Collaborators
Associated News ItemsKey publicationsJochusch WJ, Praefcke GJK, (McMahon HT, Lagnado L) (2005), “Clathrin-dependent and clathrin-independent retrieval of synaptic vesicles in retinal bipolar cells” Neuron 46:869-878 McMahon HT, Gallop JL (2005), “Membrane curvature and mechanisms of dynamic cell remodelling” Nature 438:590-596 Details Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJG, Evans PR and McMahon HT (2004), “BAR Domains as Sensors of Membrane Curvature: the Amphiphysin BAR Structure” Science 303:495-499 Publications2014Kozlov MM, Campelo F, Liska N, Chernomordik LV, Marrink SJ, McMahon HT (2014), “Mechanisms shaping cell membranes.” Curr Opin Cell Biol 29C:53-60 Details 2013Meinecke M, Boucrot E, Camdere G, Hon WC, Mittal R, McMahon HT (2013), “Cooperative recruitment of dynamin and BIN/amphiphysin/Rvs (BAR) domain-containing proteins leads to GTP-dependent membrane scission.” J Biol Chem 288(9):6651-61 Details Takeda T, Robinson IM, Savoian MM, Griffiths JR, Whetton AD, McMahon HT, Glover DM (2013), “Drosophila F-BAR protein Syndapin contributes to coupling the plasma membrane and contractile ring in cytokinesis.” Open Biol 3(8):130081 Details 2012Boucrot E, Pick A, Çamdere G, Liska N, Evergren E, McMahon HT, Kozlov MM (2012), “Membrane fission is promoted by insertion of amphipathic helices and is restricted by crescent BAR domains.” Cell 149(1):124-36 Details Chitu V, Nacu V, Charles JF, Henne WM, McMahon HT, Nandi S, Ketchum H, Harris R, Nakamura MC, Stanley ER (2012), “PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts.” Blood 120(15):3126-35 Details Sánchez-Barrena MJ, Vallis Y, Clatworthy MR, Doherty GJ, Veprintsev DB, Evans PR, McMahon HT (2012), “Bin2 is a membrane sculpting N-BAR protein that influences leucocyte podosomes, motility and phagocytosis.” PLoS One 7(12):e52401 Details 2011Boucrot E, McMahon HT (2011), “[Nucleation of clathrin-coated pits - « membrane sculptors » at work].” Med Sci (Paris) 27(2):122-5 Details Doherty GJ, Åhlund MK, Howes MT, Morén B, Parton RG, McMahon HT, Lundmark R (2011), “The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading.” Mol Biol Cell 22(22):4380-9 Details Llobet A, Gallop JL, Burden JJ, Camdere G, Chandra P, Vallis Y, Hopkins CR, Lagnado L, McMahon HT (2011), “Endophilin drives the fast mode of vesicle retrieval in a ribbon synapse.” J Neurosci 31(23):8512-9 Details Martens S, McMahon HT (2011), “C2 domains and membrane fusion.” Curr Top Membr 68:141-59 Details McMahon HT, Boucrot E (2011), “Molecular mechanism and physiological functions of clathrin-mediated endocytosis.” Nat Rev Mol Cell Biol 12(8):517-33 Details Richard JP, Leikina E, Langen R, Henne WM, Popova M, Balla T, McMahon HT, Kozlov MM, Chernomordik LV (2011), “Intracellular curvature-generating proteins in cell-to-cell fusion.” Biochem J 440(2):185-93 Details 2010Campelo F, Fabrikant G, McMahon HT, Kozlov MM (2010), “Modeling membrane shaping by proteins: focus on EHD2 and N-BAR domains.” FEBS Lett 584(9):1830-9 Details Groffen AJ, Martens S, Díez Arazola R, Cornelisse LN, Lozovaya N, de Jong AP, Goriounova NA, Habets RL, Takai Y, Borst JG, Brose N, McMahon HT, Verhage M (2010), “Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release.” Science 327(5973):1614-8 Details Henne WM, Boucrot E, Meinecke M, Evergren E, Vallis Y, Mittal R, McMahon HT (2010), “FCHo proteins are nucleators of clathrin-mediated endocytosis.” Science 328(5983):1281-4 Details Jao CC, Hegde BG, Gallop JL, Hegde PB, McMahon HT, Haworth IS, Langen R (2010), “Roles of amphipathic helices and the bin/amphiphysin/rvs (BAR) domain of endophilin in membrane curvature generation.” J Biol Chem 285(26):20164-70 Details Kozlov MM, McMahon HT, Chernomordik LV (2010), “Protein-driven membrane stresses in fusion and fission.” Trends Biochem Sci 35(12):699-706 Details McMahon HT, Kozlov MM, Martens S (2010), “Membrane curvature in synaptic vesicle fusion and beyond.” Cell 140(5):601-5 Details Mittal R, Peak-Chew SY, Sade RS, Vallis Y, McMahon HT (2010), “The acetyltransferase activity of the bacterial toxin YopJ of Yersinia is activated by eukaryotic host cell inositol hexakisphosphate.” J Biol Chem 285(26):19927-34 Details Youn JY, Friesen H, Kishimoto T, Henne WM, Kurat CF, Ye W, Ceccarelli DF, Sicheri F, Kohlwein SD, McMahon HT, Andrews BJ (2010), “Dissecting BAR domain function in the yeast Amphiphysins Rvs161 and Rvs167 during endocytosis.” Mol Biol Cell 21(17):3054-69 Details 2009Doherty GJ, McMahon HT (2009), “Mechanisms of endocytosis.” Annu Rev Biochem 78:857-902 Details Eberth A, Lundmark R, Gremer L, Dvorsky R, Koessmeier KT, McMahon HT, Ahmadian MR (2009), “A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family.” Biochem J 417(1):371-7 Details Mittal R, McMahon HT (2009), “Arrestins as adaptors for ubiquitination in endocytosis and sorting.” EMBO Rep 10(1):41-3 Details 2008Campelo F, McMahon HT, Kozlov MM (2008), “The hydrophobic insertion mechanism of membrane curvature generation by proteins.” Biophys J 95(5):2325-39 Details Doherty GJ, McMahon HT (2008), “Mediation, modulation, and consequences of membrane-cytoskeleton interactions.” Annu Rev Biophys 37:65-95 Details Lundmark R, Doherty GJ, Howes MT, Cortese K, Vallis Y, Parton RG, McMahon HT (2008), “The GTPase-activating protein GRAF1 regulates the CLIC/GEEC endocytic pathway.” Curr Biol 18(22):1802-8 Details Lundmark R, Doherty GJ, Vallis Y, Peter BJ, McMahon HT (2008), “Arf family GTP loading is activated by, and generates, positive membrane curvature.” Biochem J 414(2):189-94 Details Lynch KL, Gerona RR, Kielar DM, Martens S, McMahon HT, Martin TF (2008), “Synaptotagmin-1 utilizes membrane bending and SNARE binding to drive fusion pore expansion.” Mol Biol Cell 19(12):5093-103 Details Madsen KL, Eriksen J, Milan-Lobo L, Han DS, Niv MY, Ammendrup-Johnsen I, Henriksen U, Bhatia VK, Stamou D, Sitte HH, McMahon HT, Weinstein H, Gether U (2008), “Membrane localization is critical for activation of the PICK1 BAR domain.” Traffic 9(8):1327-43 Details Martens S, McMahon HT (2008), “Mechanisms of membrane fusion: disparate players and common principles.” Nat Rev Mol Cell Biol 9(7):543-56 Details Olesen LE, Ford MG, Schmid EM, Vallis Y, Babu MM, Li PH, Mills IG, McMahon HT, Praefcke GJ (2008), “Solitary and repetitive binding motifs for the AP2 complex alpha-appendage in amphiphysin and other accessory proteins.” J Biol Chem 283(8):5099-109 Details 2007Burtey A, Schmid EM, Ford MG, Rappoport JZ, Scott MG, Marullo S, Simon SM, McMahon HT, Benmerah A (2007), “The conserved isoleucine-valine-phenylalanine motif couples activation state and endocytic functions of beta-arrestins.” Traffic 8(7):914-31 Details Daumke O, Lundmark R, Vallis Y, Martens S, Butler PJ, McMahon HT (2007), “Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling.” Nature 449(7164):923-927 Details Henne WM, Kent HM, Ford MG, Hegde BG, Daumke O, Butler PJ, Mittal R, Langen R, Evans PR, McMahon HT (2007), “Structure and analysis of FCHo2 F-BAR domain: a dimerizing and membrane recruitment module that effects membrane curvature.” Structure 15(7):839-52 Details Martens S, Kozlov MM, McMahon HT (2007), “How synaptotagmin promotes membrane fusion.” Science 316(5828):1205-8 Details Schmid EM, McMahon HT (2007), “Integrating molecular and network biology to decode endocytosis.” Nature 448(7156):883-8 Details 2006Gallop JL, Jao CC, Kent HM, Butler PJ, Evans PR, Langen R, McMahon HT (2006), “Mechanism of endophilin N-BAR domain-mediated membrane curvature.” EMBO J 25(12):2898-910 Details Mittal R, Peak-Chew SY, McMahon HT (2006), “Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling.” Proc Natl Acad Sci U S A 103(49):18574-9 Details Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT (2006), “Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly.” PLoS Biol 4(9):e262 Details 2005Carlton JG, Bujny MV, Peter BJ, Oorschot VM, Rutherford A, Arkell RS, Klumperman J, McMahon HT, Cullen PJ (2005), “Sorting nexin-2 is associated with tubular elements of the early endosome, but is not essential for retromer-mediated endosome-to-TGN transport.” J Cell Sci 118(Pt 19):4527-39 Details Gallop JL, Butler PJ, McMahon HT (2005), “Endophilin and CtBP/BARS are not acyl transferases in endocytosis or Golgi fission.” Nature 438(7068):675-8 Details Gallop JL, McMahon HT (2005), “BAR domains and membrane curvature: bringing your curves to the BAR.” Biochem Soc Symp (72):223-31 Details Higgins MK, McMahon HT (2005), “In vitro reconstitution of discrete stages of dynamin-dependent endocytosis.” Methods Enzymol 404:597-611 Details Jockusch WJ, Praefcke GJ, McMahon HT, Lagnado L (2005), “Clathrin-dependent and clathrin-independent retrieval of synaptic vesicles in retinal bipolar cells.” Neuron 46(6):869-78 Details 2004Carlton J, Bujny M, Peter BJ, Oorschot VM, Rutherford A, Mellor H, Klumperman J, McMahon HT, Cullen PJ (2004), “Sorting nexin-1 mediates tubular endosome-to-TGN transport through coincidence sensing of high- curvature membranes and 3-phosphoinositides.” Curr Biol 14(20):1791-800 Details McMahon HT, Mills IG (2004), “COP and clathrin-coated vesicle budding: different pathways, common approaches.” Curr Opin Cell Biol 16(4):379-91 Details Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJ, Evans PR, McMahon HT (2004), “BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.” Science 303(5657):495-9 Details Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew SY, Vallis Y, Babu MM, Mills IG, McMahon HT (2004), “Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis.” EMBO J 23(22):4371-83 Details Praefcke GJ, McMahon HT (2004), “The dynamin superfamily: universal membrane tubulation and fission molecules?” Nat Rev Mol Cell Biol 5(2):133-47 Details Saint-Pol A, Yélamos B, Amessou M, Mills IG, Dugast M, Tenza D, Schu P, Antony C, McMahon HT, Lamaze C, Johannes L (2004), “Clathrin adaptor epsinR is required for retrograde sorting on early endosomal membranes.” Dev Cell 6(4):525-38 Details Tsuboi T, McMahon HT, Rutter GA (2004), “Mechanisms of dense core vesicle recapture following "kiss and run" ("cavicapture") exocytosis in insulin-secreting cells.” J Biol Chem 279(45):47115-24 Details 2003Mills IG, Praefcke GJ, Vallis Y, Peter BJ, Olesen LE, Gallop JL, Butler PJ, Evans PR, McMahon HT (2003), “EpsinR: an AP1/clathrin interacting protein involved in vesicle trafficking.” J Cell Biol 160(2):213-22 Details Stahelin RV, Long F, Peter BJ, Murray D, De Camilli P, McMahon HT, Cho W (2003), “Contrasting membrane interaction mechanisms of AP180 N-terminal homology (ANTH) and epsin N-terminal homology (ENTH) domains.” J Biol Chem 278(31):28993-9 Details 2002Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT (2002), “Curvature of clathrin-coated pits driven by epsin.” Nature 419(6905):361-6 Details Graham ME, O'Callaghan DW, McMahon HT, Burgoyne RD (2002), “Dynamin-dependent and dynamin-independent processes contribute to the regulation of single vesicle release kinetics and quantal size.” Proc Natl Acad Sci U S A 99(10):7124-9 Details Higgins MK, McMahon HT (2002), “Snap-shots of clathrin-mediated endocytosis.” Trends Biochem Sci 27(5):257-63 Details Kent HM, McMahon HT, Evans PR, Benmerah A, Owen DJ (2002), “Gamma-adaptin appendage domain: structure and binding site for Eps15 and gamma-synergin.” Structure 10(8):1139-48 Details 2001Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT (2001), “Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes.” Science 291(5506):1051-5 Details Marks B, Stowell MH, Vallis Y, Mills IG, Gibson A, Hopkins CR, McMahon HT (2001), “GTPase activity of dynamin and resulting conformation change are essential for endocytosis.” Nature 410(6825):231-5 Details Razzaq A, Robinson IM, McMahon HT, Skepper JN, Su Y, Zelhof AC, Jackson AP, Gay NJ, O'Kane CJ (2001), “Amphiphysin is necessary for organization of the excitation-contraction coupling machinery of muscles, but not for synaptic vesicle endocytosis in Drosophila.” Genes Dev 15(22):2967-79 Details Reim K, Mansour M, Varoqueaux F, McMahon HT, Südhof TC, Brose N, Rosenmund C (2001), “Complexins regulate a late step in Ca2+-dependent neurotransmitter release.” Cell 104(1):71-81 Details 2000Owen DJ, Vallis Y, Pearse BM, McMahon HT, Evans PR (2000), “The structure and function of the beta 2-adaptin appendage domain.” EMBO J 19(16):4216-27 Details 1999Marsh M, McMahon HT (1999), “The structural era of endocytosis.” Science 285(5425):215-20 Details McMahon HT (1999), “Endocytosis: an assembly protein for clathrin cages.” Curr Biol 9(9):R332-5 Details Owen DJ, Vallis Y, Noble ME, Hunter JB, Dafforn TR, Evans PR, McMahon HT (1999), “A structural explanation for the binding of multiple ligands by the alpha-adaptin appendage domain.” Cell 97(6):805-15 Details Stowell MH, Marks B, Wigge P, McMahon HT (1999), “Nucleotide-dependent conformational changes in dynamin: evidence for a mechanochemical molecular spring.” Nat Cell Biol 1(1):27-32 Details Vallis Y, Wigge P, Marks B, Evans PR, McMahon HT (1999), “Importance of the pleckstrin homology domain of dynamin in clathrin-mediated endocytosis.” Curr Biol 9(5):257-60 Details 1998Marks B, McMahon HT (1998), “Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals.” Curr Biol 8(13):740-9 Details Owen DJ, Wigge P, Vallis Y, Moore JD, Evans PR, McMahon HT (1998), “Crystal structure of the amphiphysin-2 SH3 domain and its role in the prevention of dynamin ring formation.” EMBO J 17(18):5273-85 Details Wigge P, McMahon HT (1998), “The amphiphysin family of proteins and their role in endocytosis at the synapse.” Trends Neurosci 21(8):339-44 Details 1997McMahon HT, Wigge P, Smith C (1997), “Clathrin interacts specifically with amphiphysin and is displaced by dynamin.” FEBS Lett 413(2):319-22 Details Wigge P, Köhler K, Vallis Y, Doyle CA, Owen D, Hunt SP, McMahon HT (1997), “Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis.” Mol Biol Cell 8(10):2003-15 Details Wigge P, Vallis Y, McMahon HT (1997), “Inhibition of receptor-mediated endocytosis by the amphiphysin SH3 domain.” Curr Biol 7(8):554-60 Details 1996McMahon HT, Bolshakov VY, Janz R, Hammer RE, Siegelbaum SA, Südhof TC (1996), “Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release.” Proc Natl Acad Sci U S A 93(10):4760-4 Details 1995McMahon HT, Missler M, Li C, Südhof TC (1995), “Complexins: cytosolic proteins that regulate SNAP receptor function.” Cell 83(1):111-9 Details McMahon HT, Südhof TC (1995), “Synaptic core complex of synaptobrevin, syntaxin, and SNAP25 forms high affinity alpha-SNAP binding site.” J Biol Chem 270(5):2213-7 Details 1993McMahon HT, Nicholls DG (1993), “Barium-evoked glutamate release from guinea-pig cerebrocortical synaptosomes.” J Neurochem 61(1):110-5 Details McMahon HT, Ushkaryov YA, Edelmann L, Link E, Binz T, Niemann H, Jahn R, Südhof TC (1993), “Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein.” Nature 364(6435):346-9 Details 1992McMahon HT, Foran P, Dolly JO, Verhage M, Wiegant VM, Nicholls DG (1992), “Tetanus toxin and botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-enkephalin release from synaptosomes. Clues to the locus of action.” J Biol Chem 267(30):21338-43 Details 1991McMahon HT, Nicholls DG (1991), “The bioenergetics of neurotransmitter release.” Biochim Biophys Acta 1059(3):243-64 Details McMahon HT, Nicholls DG (1991), “Transmitter glutamate release from isolated nerve terminals: evidence for biphasic release and triggering by localized Ca2+.” J Neurochem 56(1):86-94 Details Verhage M, McMahon HT, Ghijsen WE, Boomsma F, Scholten G, Wiegant VM, Nicholls DG (1991), “Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals.” Neuron 6(4):517-24 Details 1990McMahon HT, Nicholls DG (1990), “The relationship between cytoplasmic free Ca2+ and the release of glutamate from synaptosomes.” Biochem Soc Trans 18(3):375-7 Details McMahon HT, Nicholls DG (1990), “Glutamine and aspartate loading of synaptosomes: a reevaluation of effects on calcium-dependent excitatory amino acid release.” J Neurochem 54(2):373-80 Details McMahon HT, Rosenthal L, Meldolesi J, Nicholls DG (1990), “Alpha-latrotoxin releases both vesicular and cytoplasmic glutamate from isolated nerve terminals.” J Neurochem 55(6):2039-47 Details 1989McMahon HT, Barrie AP, Lowe M, Nicholls DG (1989), “Glutamate release from guinea-pig synaptosomes: stimulation by reuptake-induced depolarization.” J Neurochem 53(1):71-9 Details Tibbs GR, Barrie AP, Van Mieghem FJ, McMahon HT, Nicholls DG (1989), “Repetitive action potentials in isolated nerve terminals in the presence of 4-aminopyridine: effects on cytosolic free Ca2+ and glutamate release.” J Neurochem 53(6):1693-9 Details 1988Kauppinen RA, McMahon HT, Nicholls DG (1988), “Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia.” Neuroscience 27(1):175-82 Details |