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UGA BCMB 8020 - Hurley

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Cell, Vol. 111, 143–146, October 18, 2002, Copyright 2002 by Cell PressMinireviewEndocytosis: Driving Membranesaround the Bendpit into a vesicle? The process of clathrin polymerizinginto a basket, linked to the membrane via adaptor pro-teins, is thought to physically pull the membrane inwardJames H. Hurley1,3and Beverly Wendland2,31Laboratory of Molecular BiologyNational Institute of Diabetes and Digestive andKidney Diseases toward the cytosol to initiate formation of an endocyticvesicle. Later, the accessory proteins amphiphysin, en-National Institutes of HealthBethesda, Maryland 20892 dophilin, and dynamin are concentrated at the narrow,highly curved membrane “necks” of deeply invaginated2Department of BiologyJohns Hopkins University clathrin-coated pits, where they function in the final scis-sion step that converts the coated pit into a coated3400 North Charles StreetBaltimore, Maryland 21218 vesicle. The De Camilli and Hinshaw labs found thatthese three proteins can each, on their own, promotethe tubulation or vesiculation of membranes (reviewedin Hinshaw, 2000). This is consistent with amphiphysin,When a nascent vesicle buds, the membrane mustendophilin, and dynamin directly altering the conforma-curve. Several mechanisms have been proposed fortion of the lipid bilayer. Various mechanisms for thiscurvature creation or stabilization. Structural analysisprocess have been proposed, ranging from oligomeriza-of the ENTH domain of the endocytic protein epsintion-driven mechanical deformation of the lipid bilayerhas suggested a new mechanism, in which the ENTHby dynamin to enzymatic lipid remodeling activities ofdomain pushes its way into membranes, thus bendingendophilin that alter the biophysical properties of thethem into shape.lipid bilayer.In order for a protein to effect membrane curvature,The plasma membrane of cells presents a barrier to theit must first bind to membranes. Each of these tubulatingentry of large water-soluble particles and nutrients, suchproteins binds to membranes, often by interacting spe-as iron, folate, and LDL-cholesterol. This barrier is over-cifically with the phosphoinositide PtdIns(4,5)P2(PIP2).come through endocytosis, the process by which por-Recombinant dynamin, amphiphysin, or endophilin cantions of the plasma membrane and extracellular fluidtransform artificial liposomes containing acidic phos-are taken up into a cell. Endocytosis is also critical forpholipids and/or PIP2into protein-wrapped tubules. Itmany physiological responses; for instance, downregu-has been suggested that dynamin promotes scissionlation of certain signaling receptors. Endocytosis canthrough a combination of binding activities, GTP-drivenoccur via several distinct pathways. The best-character-conformational changes of the dynamin oligomer, and ad-ized pathway depends upon the cytosolic protein com-ditional functions of associated proteins that conspire to-plex clathrin, along with its accessory factors (reviewedgether to promote fission of the membrane (Hinshaw,in Brodsky et al., 2001; Kirchhausen, 2000). The process2000).begins by gathering together plasma membrane pro-One concern about the biophysical contortions of theteins and lipids through interactions with cytosolic adap-membrane at the constricted neck is the high degreetors and accessory factors. Some of these cytosolicof curvature, both positive (around the circumferencefactors bind to clathrin and stimulate its polymerizationof the neck) and negative (the sharp bend as viewedinto a spherical basket of pentagons and hexagons. Asperpendicular to the plasma membrane) (see Figure 1).the endocytic vesicle forms, the plasma membrane andOne model that tried to account for these extremesassociated proteins and adjacent extracellular fluid arein curvature suggested that the enzymatic activity ofpulled inward into the cytosol. Upon scission, theendophilin (the condensation of lysophosphatidic acid ⫹clathrin-coated vesicle is released into the cytoplasmacyl CoA to form phosphatidic acid) altered the curva-(Figure 1).ture of the membrane by physically changing the com-Clathrin accessory factors generally exhibit multipleposition of the phospholipids from “inverted coneprotein interaction domains that allow them to form ashaped” to “cone shaped,” and thus affected the inher-web of contacts. Clathrin-coated vesicles are not highlyent disposition of the membrane (Schmidt et al., 1999).enriched for accessory factors, thus, these factors areHowever, this model is now disfavored since endophilinnot structural, but rather perform regulatory or catalyticlacking the enzymatic activity can still tubulate mem-functions at specific stages in endocytosis. One acces-branes (Farsad et al., 2001). These final scission eventssory factor, epsin, was discovered in 1998 by virtue ofare likely to require quite different changes in membraneits binding to another accessory factor, eps15 (Chen etstructure and curvature as compared to those that initi-al., 1998). Epsin has become a focus of interest due toate bud formation, to which we now turn our attention.its interactions with membranes, accessory proteins,ENTH Domainsclathrin, ubiquitin, and possibly certain cargo proteinsStudies of epsin by the De Camilli lab (Chen et al., 1998)(Wendland, 2002).and other groups have indicated a role for epsin in endo-Membranes Get Bent out of Shapecytosis, in particular the highly conserved amino termi-How do changes in curvature of the membrane bilayernal region (Wendland et al., 1999), which was christenedoccur during bud formation and resolution of the coatedthe epsin N-terminal homology (ENTH) domain (Kay etal., 1998). While many studies have indicated a central3Correspondence: [email protected] (J.H.H.); [email protected] (B.W.)role for epsin in the process of endocytosis, the preciseCell144Figure 1. The Process of Endocytosis Is Depicted as a Series of Events Beginning with the Initiation of a Bud and Culminating in the Releaseof a Clathrin-Coated Vesicle into the CytoplasmBud initiation is thought to occur in part by the association of epsin as well as adaptor proteins like AP2 binding sorting signals on receptortails. As the bud forms and constricts, the activities of other proteins such as endophilin and amphiphysin cooperate at the edge of thegrowing clathrin coat to remodel the lipids at the bud neck. The GTPase activity of dynamin is required for the scission event that separatesthe vesicle from the plasma membrane. Negative


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