After passing through the Golgi complex, secretory cargo is packaged into post-Golgi transport intermediates (post-Golgi), which translocate plus-end directed along microtubules to the plasma membrane.
There at least two classes of clathrin coated vesicles in cells, one predominantly Golgi-associated, involved in budding from the trans-Golgi network and the other at the plasma membrane. Here the clathrin-coated vesicles emerging from the Golgi apparatus are triggered by the heterotetrameric adaptor protein complex, AP-1 at the trans-Golgi network membrane. The cargo can be transmembrane, membrane associated or golgi luminal proteins. Each step in the vesicle sculpting pathway, gathers cargo and clathrin triskeletons, until a complete vesicular sphere is formed. With the scission of the membrane the vesicle is released and eventually losses its clathrin coat.
Sohda M, Misumi Y, Yamamoto A, Yano A, Nakamura N, Ikehara Y.; ''Identification and characterization of a novel Golgi protein, GCP60, that interacts with the integral membrane protein giantin.''; PubMedEurope PMCScholia
Suzuki K, Verma IM.; ''Phosphorylation of SNAP-23 by IkappaB kinase 2 regulates mast cell degranulation.''; PubMedEurope PMCScholia
Puri N, Roche PA.; ''Ternary SNARE complexes are enriched in lipid rafts during mast cell exocytosis.''; PubMedEurope PMCScholia
Hirst J, Bright NA, Rous B, Robinson MS.; ''Characterization of a fourth adaptor-related protein complex.''; PubMedEurope PMCScholia
Zhu Y, Traub LM, Kornfeld S.; ''ADP-ribosylation factor 1 transiently activates high-affinity adaptor protein complex AP-1 binding sites on Golgi membranes.''; PubMedEurope PMCScholia
Ungewickell E, Ungewickell H, Holstein SE, Lindner R, Prasad K, Barouch W, Martin B, Greene LE, Eisenberg E.; ''Role of auxilin in uncoating clathrin-coated vesicles.''; PubMedEurope PMCScholia
Musacchio A, Smith CJ, Roseman AM, Harrison SC, Kirchhausen T, Pearse BM.; ''Functional organization of clathrin in coats: combining electron cryomicroscopy and X-ray crystallography.''; PubMedEurope PMCScholia
Takatsu H, Sakurai M, Shin HW, Murakami K, Nakayama K.; ''Identification and characterization of novel clathrin adaptor-related proteins.''; PubMedEurope PMCScholia
Bryant NJ, Govers R, James DE.; ''Regulated transport of the glucose transporter GLUT4.''; PubMedEurope PMCScholia
Antonin W, Holroyd C, Fasshauer D, Pabst S, Von Mollard GF, Jahn R.; ''A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function.''; PubMedEurope PMCScholia
Starcevic M, Dell'Angelica EC.; ''Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1).''; PubMedEurope PMCScholia
Lee DW, Zhao X, Zhang F, Eisenberg E, Greene LE.; ''Depletion of GAK/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors.''; PubMedEurope PMCScholia
Hartmann-Stühler C, Prange R.; ''Hepatitis B virus large envelope protein interacts with gamma2-adaptin, a clathrin adaptor-related protein.''; PubMedEurope PMCScholia
Acton SL, Wong DH, Parham P, Brodsky FM, Jackson AP.; ''Alteration of clathrin light chain expression by transfection and gene disruption.''; PubMedEurope PMCScholia
Salinas E, Quintanar-Stephano A, Córdova LE, Ouintanar JL.; ''Allergen-sensitization increases mast-cell expression of the exocytotic proteins SNAP-23 and syntaxin 4, which are involved in histamine secretion.''; PubMedEurope PMCScholia
Döring T, Gotthardt K, Stieler J, Prange R.; ''γ2-Adaptin is functioning in the late endosomal sorting pathway and interacts with ESCRT-I and -III subunits.''; PubMedEurope PMCScholia
Borner GH, Harbour M, Hester S, Lilley KS, Robinson MS.; ''Comparative proteomics of clathrin-coated vesicles.''; PubMedEurope PMCScholia
Seaman MN, Sowerby PJ, Robinson MS.; ''Cytosolic and membrane-associated proteins involved in the recruitment of AP-1 adaptors onto the trans-Golgi network.''; PubMedEurope PMCScholia
Burgos PV, Mardones GA, Rojas AL, daSilva LL, Prabhu Y, Hurley JH, Bonifacino JS.; ''Sorting of the Alzheimer's disease amyloid precursor protein mediated by the AP-4 complex.''; PubMedEurope PMCScholia
Maier O, Knoblich M, Westermann P.; ''Dynamin II binds to the trans-Golgi network.''; PubMedEurope PMCScholia
Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM.; ''Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.''; PubMedEurope PMCScholia
Aguilar RC, Boehm M, Gorshkova I, Crouch RJ, Tomita K, Saito T, Ohno H, Bonifacino JS.; ''Signal-binding specificity of the mu4 subunit of the adaptor protein complex AP-4.''; PubMedEurope PMCScholia
Hirst J, Lindsay MR, Robinson MS.; ''GGAs: roles of the different domains and comparison with AP-1 and clathrin.''; PubMedEurope PMCScholia
Farsad K, Ringstad N, Takei K, Floyd SR, Rose K, De Camilli P.; ''Generation of high curvature membranes mediated by direct endophilin bilayer interactions.''; PubMedEurope PMCScholia
Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L.; ''Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.''; PubMedEurope PMCScholia
The ferritin complex is an oligomer of 24 subunits with light and heavy chains. The structural features of ferritin arise from the combination in various ratios of two subunits, H and L, which differ in size, amino acid composition, surface charge, and immunoreactivity. A corollary related differences in ferritin iron content to the functional efficiency of one of the two subunits for storing iron. In humans the H subunit is associated with a lower pI and lower iron content, and predominates in heart tissue, whereas the L subunit is associated with a higher pI and higher iron content, and predominates in the liver.
The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5'-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
ARF1 helps to recruit AP-1 to Golgi membrane. AP-1 is not alone in this process of establishing a docking complex at the trans-Golgi Network. This section of the Golgi membrane will be where the new vesicle will be built and loaded.
Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the vesicle. The number of clathrin triskelions required to sculpt a vesicle appears to be variable, but has been estimated to require 36 - 60 triskelions assocaited with 30 - 66 AP-1 complexes. Here a ~380 angstroms vesicle is represented with 48 clathrin triskelions and 52 AP-1 complexes.
Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the Golgi-associated vesicle membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings.
Dynamin is recruited to the growing vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle.
The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the Golgi-associated vesicle membrane.
The ubiquitously expressed protein complexes, named biogenesis of lysosome-related organelles complex or BLOC are required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules.
The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the lysosome membrane.
Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the lysosome vesicle. Here only 5 clathrin triskelions are represented, though in reality many more would be involved in sculpting an entire vesicle.
Dynamin is recruited to the growing lysosome destined vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle.
Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the lysosome membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings.
AP-4 complex subunit mu-1 (AP4M1) can recognise and interact with tyrosine-based (YXXphi) sorting signals found within the cytoplasmic tails of integral membrane proteins such as the amyloid precursor protein (APP), implicated in Alzheimer's disease. Once bound to AP4M1, APP is transported from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein. Disruption of this interaction decreases localisation of APP to endosomes and enhances gamma-secretase-catalysed cleavage of APP to the pathogenic amyloid-beta peptide (Burgos et al. 2010).
The family of heterotetrameric adaptor protein (AP) complexes function as vesicle coat components, involved in targeting cargo proteins from post-Golgi compartments to the endosomal-lysosomal system. Adaptor protein 4 (AP4) is the most recently discovered and least characterised member of this family. AP4 consists of four subunits; two large adaptins (AP4E1 and AP4B1), a medium adaptin (AP4M1) and a small adaptin (AP4S1). The medium (mu) adaptins of all AP complexes can recognise and interact with tyrosine-based (YXXphi) sorting signals found within the cytoplasmic tails of integral membrane proteins (Aguilar et al. 2001, Hirst et al. 1999). The amyloid precursor protein (APP), implicated in Alzheimer's disease, contains such a signal in its cytoplasmic tail. It can therefore bind to AP4M1 of the AP4 complex and subsequently, be transported from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein. Disruption of the this interaction decreases localisation of APP to endosomes and enhances gamma-secretase-catalysed cleavage of APP to the pathogenic amyloid-beta peptide (Burgos et al. 2010).
Defects in AP4M1 can cause cerebral palsy, spastic quadriplegic 3 (CPSQ3; MIM:612936), a non-progressive disorder of movement and/or posture resulting from defects in CNS development (Verkerk et al. 2009). Defects in AP4S1 can cause cerebral palsy, spastic quadriplegic 6 (CPSQ6; MIM:614067), a neurodevelopmental disorder characterised by hypertonia and spasticity, and severe mental retardation with poor or absent speech development (Abou Jamra et al. 2011).
Clathrin-coated vesicles (CCVs) originating from the trans-Golgi network (TGN) provide a major transport pathway from the secretory system to endosomes/lysosomes. Clavesin 1 and 2 (CLVS1 and 2) are enriched on CCVs and form a complex with clathrin heavy chain (CHC) and adaptor protein-1 (AP1) complex, major coat components of TGN-derived CCVs. The complex can bind phosphatidylinositol 3,5-bisphosphate (PIP2), a phospholipid localised to late endosomes and lysosomes. This interaction is thought to assist the transport of cytosolic cargo proteins to the endosomal network (Katoh et al. 2009).
AP-1 complex subunit gamma-like 2 (AP1G2) is an 87-kDa protein that is similar to gamma-adaptin (AP1G1), a large chain of the AP1 clathrin-associated adaptor complex, both in primary structure (60% amino acid identity) and domain organisation (Takatsu et al. 1998). AP1G2 can be viewed as a putative endosomal sorting and trafficking adaptor that is specifically required for degradative endocytic trafficking and may help in maintaining homeostasis of the multivesicular body (MVB) protein-sorting pathway. AP1G2 specifically interacts with the core ESCRT subunits hepatocyte growth factor-regulated tyrosine kinase substrate (HGS, aka HRS) and charged multivesicular body protein 2a (CHMP2A aka hVps2-1), involved in MVB processing (Doring et al. 2010).
AP1G2 is also able to bind the large envelope protein (surface protein S) of the hepatitis B virus (HBV), a protein that plays an important role in viral budding (Hartmann-Stuhler & Prange 2001). Disruption of this binding can inhibit virus production (Rost et al. 2006). Thus, AP1G2 may play a role in L-mediated processes of viral biogenesis or pathogenesis.
Golgi resident protein GCP60 (ACBD3) is a Golgi membrane-associated protein thought to be involved in the maintenance of the Golgi structure by interacting with Golgin subfamily B member 1 (GOLGB1, giantin), which may mediate protein transport between the endoplasmic reticulum and the Golgi (Sohda et al. 2001).
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The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5'-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
Vesicle Destined
CargoVesicle Destined
Cargovesicle interacting
proteinsDestined
Cargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp ComplexDestined
Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin ComplexSecretory granule docking and fusion
complexPlasma membrane vesicle docking and
fusion complexSecretory granule docking and fusion
complexAnnotated Interactions
Vesicle Destined
Cargovesicle interacting
proteinsDestined
Cargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp ComplexDestined
Cargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp ComplexDestined
Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin ComplexDestined
Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin ComplexDestined
Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin ComplexDefects in AP4M1 can cause cerebral palsy, spastic quadriplegic 3 (CPSQ3; MIM:612936), a non-progressive disorder of movement and/or posture resulting from defects in CNS development (Verkerk et al. 2009). Defects in AP4S1 can cause cerebral palsy, spastic quadriplegic 6 (CPSQ6; MIM:614067), a neurodevelopmental disorder characterised by hypertonia and spasticity, and severe mental retardation with poor or absent speech development (Abou Jamra et al. 2011).
AP1G2 is also able to bind the large envelope protein (surface protein S) of the hepatitis B virus (HBV), a protein that plays an important role in viral budding (Hartmann-Stuhler & Prange 2001). Disruption of this binding can inhibit virus production (Rost et al. 2006). Thus, AP1G2 may play a role in L-mediated processes of viral biogenesis or pathogenesis.
Secretory granule docking and fusion
complexPlasma membrane vesicle docking and
fusion complexSecretory granule docking and fusion
complex