Dr Harvey McMahon FRS

Harvey McMahon

University position

MRC Programme Leader

Dr Harvey McMahon FRS is pleased to consider applications from prospective PhD students.

Institutes

Medical Research Council Laboratory of Molecular Biology

Email

hmm@mrc-lmb.cam.ac.uk

Home page

http://www.endocytosis.org/ (personal home page)

Research Theme

Cellular and Molecular Neuroscience

Interests

Molecular 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
Depiction of a protein interaction network underlying nerve function
Click image to view full-size

Research Focus

Keywords

synapse

exocytosis

endocytosis

mental retardation

protein networks

Clinical conditions

Genetic disorders

Huntington's disease

Parkinson's disease

Prion diseases

Equipment

Analytical 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

Cambridge

Roger Barker

Leon Lagnado

Associated News Items


    Key publications

    Jochusch 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

    Publications

    2014

    Kozlov MM, Campelo F, Liska N, Chernomordik LV, Marrink SJ, McMahon HT (2014), “Mechanisms shaping cell membranes.” Curr Opin Cell Biol 29C:53-60 Details

    2013

    Meinecke 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

    2012

    Boucrot 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

    2011

    Boucrot 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

    2010

    Campelo 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

    2009

    Doherty 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

    2008

    Campelo 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

    2007

    Burtey 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

    2006

    Gallop 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

    2005

    Carlton 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

    2004

    Carlton 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

    2003

    Mills 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

    2002

    Ford 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

    2001

    Ford 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

    2000

    Owen 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

    1999

    Marsh 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

    1998

    Marks 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

    1997

    McMahon 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

    1996

    McMahon 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

    1995

    McMahon 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

    1993

    McMahon 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

    1992

    McMahon 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

    1991

    McMahon 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

    1990

    McMahon 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

    1989

    McMahon 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

    1988

    Kauppinen 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