Genomes and Genes
Gene Symbol: alpha-adaptin
Description: adaptor related protein complex 2 subunit alpha 1
Alias: ADTAA, AP2-ALPHA, CLAPA1, AP-2 complex subunit alpha-1, 100 kDa coated vesicle protein A, adapter-related protein complex 2 alpha-1 subunit, adapter-related protein complex 2 subunit alpha-1, adaptin, alpha A, adaptor protein complex AP-2 subunit alpha-1, adaptor related protein complex 2 alpha 1 subunit, alpha-adaptin A, alpha1-adaptin, clathrin assembly protein complex 2 alpha-A large chain, clathrin-associated/assembly/adaptor protein, large, alpha 1, plasma membrane adaptor HA2/AP2 adaptin alpha A subunit
- Chaudhuri R, Mattera R, Lindwasser O, Robinson M, Bonifacino J. A basic patch on alpha-adaptin is required for binding of human immunodeficiency virus type 1 Nef and cooperative assembly of a CD4-Nef-AP-2 complex. J Virol. 2009;83:2518-30 pubmed publisher..This cooperativity explains how Nef is able to efficiently downregulate CD4 despite weak binary interactions between components of the tripartite complex. ..
- Lindwasser O, Smith W, Chaudhuri R, Yang P, Hurley J, Bonifacino J. A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2. J Virol. 2008;82:1166-74 pubmed
- Berlioz Torrent C, Shacklett B, Erdtmann L, Delamarre L, Bouchaert I, Sonigo P, et al. Interactions of the cytoplasmic domains of human and simian retroviral transmembrane proteins with components of the clathrin adaptor complexes modulate intracellular and cell surface expression of envelope glycoproteins. J Virol. 1999;73:1350-61 pubmed
- Chen H, Fre S, Slepnev V, Capua M, Takei K, Butler M, et al. Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature. 1998;394:793-7 pubmed..We propose that epsin may participate, together with Eps15, in the molecular rearrangement of the clathrin coats that are required for coated-pit invagination and vesicle fission. ..
- Brett T, Traub L, Fremont D. Accessory protein recruitment motifs in clathrin-mediated endocytosis. Structure. 2002;10:797-809 pubmed..A mechanism of clathrin assembly regulation is suggested by three different AP-2 engagement modes. ..
- Adamopoulos P, Kontos C, Diamantopoulos M, Scorilas A. Molecular cloning of novel transcripts of the adaptor-related protein complex 2 alpha 1 subunit (AP2A1) gene, using Next-Generation Sequencing. Gene. 2018;678:55-64 pubmed publisher..Undoubtedly, the exact role of these new APA1 splice variants merits elucidation. ..
- Wigge P, Vallis Y, McMahon H. Inhibition of receptor-mediated endocytosis by the amphiphysin SH3 domain. Curr Biol. 1997;7:554-60 pubmed..We propose that amphiphysin is not only required for synaptic-vesicle endocytosis, but might also be a key player in dynamin recruitment in all cells undergoing receptor-mediated endocytosis. ..
- Wang C, Zhao D, Shah S, Yang W, Li C, Yang L. Proteome Analysis of Potential Synaptic Vesicle Cycle Biomarkers in the Cerebrospinal Fluid of Patients with Sporadic Creutzfeldt-Jakob Disease. Mol Neurobiol. 2017;54:5177-5191 pubmed publisher..We hope that promising biomarkers can be identified in the CSF of patients with sCJD and other neurodegenerative disorders to help predict disease progression. ..
- Page L, Robinson M. Targeting signals and subunit interactions in coated vesicle adaptor complexes. J Cell Biol. 1995;131:619-30 pubmed..These results indicate that the adaptor subunits act in concert to target the complex to the appropriate membrane. ..
- Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H, et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol. 2003;5:819-26 pubmed..These results suggest that in addition to regulating microtubule assembly, CRMP-2 is involved in polarized Numb-mediated endocytosis of proteins such as L1. ..
- Kameoka M, Kitagawa Y, Utachee P, Jinnopat P, Dhepakson P, Isarangkura Na Ayuthaya P, et al. Identification of the suppressive factors for human immunodeficiency virus type-1 replication using the siRNA mini-library directed against host cellular genes. Biochem Biophys Res Commun. 2007;359:729-34 pubmed..We also discuss the possible mechanisms by which those cellular proteins regulate viral replication. ..
- Krauss M, Haucke V. Functional assay of effectors of ADP ribosylation factor 6 during clathrin/AP-2 coat recruitment to membranes. Methods Enzymol. 2005;404:388-98 pubmed..These methods shall help to mechanistically dissect the role of Arf6 in regulating exo-endocytic vesicle cycling at synapses and in related membrane trafficking events. ..
- Lu W, Ziff E. PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking. Neuron. 2005;47:407-21 pubmed..We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking. ..
- Stratton J, Kumar R, Sinha S, Shah P, Stykel M, Shapira Y, et al. Purification and Characterization of Schwann Cells from Adult Human Skin and Nerve. Eneuro. 2017;4: pubmed publisher..Taken together, we demonstrate that adult hSk-SCs are genetically and phenotypically indistinguishable to hN-SCs. ..
- Miller S, Mathiasen S, Bright N, Pierre F, Kelly B, Kladt N, et al. CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. Dev Cell. 2015;33:163-75 pubmed publisher..CALM is thus a major factor in controlling CCV size and maturation and hence in determining the rates of endocytic cargo uptake. ..
- Zhang J, Williams T. Identification and regulation of tissue-specific cis-acting elements associated with the human AP-2alpha gene. Dev Dyn. 2003;228:194-207 pubmed..Taken together, these findings indicate that cell:cell communication within the forelimb is altered in the absence of AP-2alpha and reveal novel regulatory potential for AP-2alpha in limb development. ..
- Han T, Yang C, Chang K, Zhang D, Imam F, Rana T. Identification of novel genes and networks governing hematopoietic stem cell development. EMBO Rep. 2016;17:1814-1828 pubmed
- Cullis D, Philip B, Baleja J, Feig L. Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. J Biol Chem. 2002;277:49158-66 pubmed..These findings suggest that Rab11-FIP2 may participate in the coupling of receptor-mediated endocytosis to the subsequent sorting of receptor-containing vesicles in endosomes. ..
- Yano H, Lee F, Kong H, Chuang J, Arevalo J, Perez P, et al. Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor. J Neurosci. 2001;21:RC125 pubmed..The association of Trk receptors with components of cytoplasmic dynein suggests that transport of neurotrophins during vesicular trafficking may occur through a direct interaction of the Trk receptor with the dynein motor machinery. ..
- McLaughlin N, Banerjee A, Kelher M, Gamboni Robertson F, Hamiel C, Sheppard F, et al. Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol. 2006;176:7039-50 pubmed..We conclude that PAF signaling requires CME, beta-arrestin-1 recruitment of a p38 MAPK signalosome, and specific actin bundle formation at the PAFR for transduction before endosomal scission. ..
- Ren X, Park S, Bonifacino J, Hurley J. How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4. elife. 2014;3:e01754 pubmed publisher..DOI: http://dx.doi.org/10.7554/eLife.01754.001. ..
- Mitchell R, Chaudhuri R, Lindwasser O, Tanaka K, Lau D, Murillo R, et al. Competition model for upregulation of the major histocompatibility complex class II-associated invariant chain by human immunodeficiency virus type 1 Nef. J Virol. 2008;82:7758-67 pubmed publisher..These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II. ..
- Sakaguchi K, Okabayashi Y, Kasuga M. Shc mediates ligand-induced internalization of epidermal growth factor receptors. Biochem Biophys Res Commun. 2001;282:1154-60 pubmed..These results suggest, therefore, the implication of Shc in ligand-induced endocytosis of EGF receptors in intact cells. ..
- Boehm M, Bonifacino J. Adaptins: the final recount. Mol Biol Cell. 2001;12:2907-20 pubmed..Finally, we extend our survey to adaptin-related proteins such as the GGAs and stonins, which contain domains homologous to the adaptins. ..
- John B, Herrin B, Raman C, Wang Y, Bobbitt K, Brody B, et al. The B cell coreceptor CD22 associates with AP50, a clathrin-coated pit adapter protein, via tyrosine-dependent interaction. J Immunol. 2003;170:3534-43 pubmed..In conclusion, these studies demonstrate that internalization of CD22 is dependent on its association with the AP-2 complex via tyrosine-based internalization motifs. ..
- Vleurick L, Pezet A, Kuhn E, Decuypere E, Edery M. A beta-turn endocytic code is required for optimal internalization of the growth hormone receptor but not for alpha-adaptin association. Mol Endocrinol. 1999;13:1823-31 pubmed..Finally, the present study illustrates that functional amino acid motifs of receptors can be derived from comparative studies. ..
- Fan G, Yang W, Wang X, Qian Q, Richmond A. Identification of a motif in the carboxyl terminus of CXCR2 that is involved in adaptin 2 binding and receptor internalization. Biochemistry. 2001;40:791-800 pubmed..These data demonstrate a role for the LLKIL motif in the carboxyl terminus of CXCR2 in receptor internalization and cell chemotaxis and imply a role for adaptin 2 in the endocytosis of CXCR2. ..
- Nandez R, Balkin D, Messa M, Liang L, Paradise S, Czapla H, et al. A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells. elife. 2014;3:e02975 pubmed publisher..These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations. ..
- Kirchhausen T. Clathrin. Annu Rev Biochem. 2000;69:699-727 pubmed..This review summarizes and illustrates the recent structural results and outlines what is known about coated-vesicle assembly in the context of this information. ..
- Stove V, Van de Walle I, Naessens E, Coene E, Stove C, Plum J, et al. Human immunodeficiency virus Nef induces rapid internalization of the T-cell coreceptor CD8alphabeta. J Virol. 2005;79:11422-33 pubmed..The Nef-mediated internalization of receptors, such as CD4, major histocompatibility complex class I, CD28, and CD8alphabeta, may contribute to the subversion of the host immune system and progression towards AIDS. ..
- Rosse C, L Hoste S, Offner N, Picard A, Camonis J. RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate epsin during the switch off of endocytosis in mitosis. J Biol Chem. 2003;278:30597-604 pubmed..We propose that RLIP/RalBP1 is used as a platform by the mitotic cdk1 to facilitate the phosphorylation of Epsin, which makes Epsin incompetent for endocytosis during mitosis, when endocytosis is switched off...
- Ono A. HIV-1 Assembly at the Plasma Membrane: Gag Trafficking and Localization. Future Virol. 2009;4:241-257 pubmed..In addition, findings on Gag association with specific plasma membrane domains are discussed in light of potential roles in cell-to-cell transmission. ..
- Buss F, Arden S, Lindsay M, Luzio J, Kendrick Jones J. Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis. EMBO J. 2001;20:3676-84 pubmed..Myosin VI is the first motor protein to be identified associated with clathrin-coated pits/vesicles and shown to modulate clathrin-mediated endocytosis. ..
- Leprince C, Romero F, Cussac D, Vayssiere B, Berger R, Tavitian A, et al. A new member of the amphiphysin family connecting endocytosis and signal transduction pathways. J Biol Chem. 1997;272:15101-5 pubmed..This hypothesis is strengthened by the ability of BRAMP2 to interact with the p21(ras) exchange factor SOS, in vitro, as a possible point of interconnection between the endocytic and signaling pathways. ..
- Yoshida H, Nagaoka A, Nakamura S, Sugiyama Y, Okada Y, Inoue S. Murine homologue of the human KIAA1199 is implicated in hyaluronan binding and depolymerization. FEBS Open Bio. 2013;3:352-6 pubmed publisher..We conclude that like hKIAA1199, mKiaa1199 is a hyaladherin, leading to HA depolymerization. ..
- Boll W, Rapoport I, Brunner C, Modis Y, Prehn S, Kirchhausen T. The mu2 subunit of the clathrin adaptor AP-2 binds to FDNPVY and YppØ sorting signals at distinct sites. Traffic. 2002;3:590-600 pubmed..These results suggest the possibility that low-density lipoprotein receptor uptake may be modulated specifically and independently of other proteins in the clathrin pathway. ..
- Sitaram A, Piccirillo R, Palmisano I, Harper D, Dell Angelica E, Schiaffino M, et al. Localization to mature melanosomes by virtue of cytoplasmic dileucine motifs is required for human OCA2 function. Mol Biol Cell. 2009;20:1464-77 pubmed publisher..We conclude that OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. ..
- Lee W, Rohrer J, Kornfeld R, Kornfeld S. Multiple signals regulate trafficking of the mannose 6-phosphate-uncovering enzyme. J Biol Chem. 2002;277:3544-51 pubmed..These findings indicate that the YAYHPLQE motif is recognized at several sorting sites, including the trans-Golgi network, the plasma membrane, and the endosome. ..
- Zhao Z, Sagare A, Ma Q, Halliday M, Kong P, Kisler K, et al. Central role for PICALM in amyloid-Î² blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015;18:978-87 pubmed publisher..Thus, PICALM regulates AÎ² BBB transcytosis and clearance, which has implications for AÎ² brain homeostasis and clearance therapy. ..
- Elhamdani A, Azizi F, Solomaha E, Palfrey H, Artalejo C. Two mechanistically distinct forms of endocytosis in adrenal chromaffin cells: Differential effects of SH3 domains and amphiphysin antagonism. FEBS Lett. 2006;580:3263-9 pubmed..These data confirm that dynamin-1 dependent RE is independent of clathrin and show that amphiphysin is exclusively associated with clathrin and dynamin-2-dependent SE. ..
- Gorski J, Savage K, Mulligan J, McDade S, Blayney J, Ge Z, et al. Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis. Nucleic Acids Res. 2011;39:9536-48 pubmed publisher..These data suggest a model, whereby BRCA1 is present on defined promoters as part of an inactive complex poised to respond to various genotoxic stimuli. ..
- Yoshida H, Nagaoka A, Kusaka Kikushima A, Tobiishi M, Kawabata K, Sayo T, et al. KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Sci U S A. 2013;110:5612-7 pubmed publisher..These data suggest that KIAA1199 is a unique hyaladherin with a key role in HA catabolism in the dermis of the skin and arthritic synovium. ..
- Robinson M. Cloning of cDNAs encoding two related 100-kD coated vesicle proteins (alpha-adaptins). J Cell Biol. 1989;108:833-42 pubmed..Antipeptide antibodies are now being raised to find out whether the proteins are localized in functionally distinct populations of endocytic coated vesicles. ..
- Tebar F, Bohlander S, Sorkin A. Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol Biol Cell. 1999;10:2687-702 pubmed..Altogether, the data suggest that CALM is an important component of coated pit internalization machinery, possibly involved in the regulation of clathrin recruitment to the membrane and/or the formation of the coated pit. ..
- Jacob R, Johnson A, Pawlak E, Dirk B, Van Nynatten L, Haeryfar S, et al. The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis. Virology. 2017;509:1-10 pubmed publisher..Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions. ..
- Krieger J, Taylor P, Gajadhar A, Guha A, Moran M, McGlade C. Identification and selected reaction monitoring (SRM) quantification of endocytosis factors associated with Numb. Mol Cell Proteomics. 2013;12:499-514 pubmed publisher..Hence, quantitative mass spectrometric analysis of Numb protein-protein interactions has provided new insights into the assembly and regulation of protein complexes important in development and cancer. ..
- Anand D, Lachke S. Systems biology of lens development: A paradigm for disease gene discovery in the eye. Exp Eye Res. 2017;156:22-33 pubmed publisher..We anticipate that application of a similar approach to other ocular tissues such as the retina and the cornea, and even other organ systems, will significantly impact disease gene discovery. ..
- Rosenthal J, Chen H, Slepnev V, Pellegrini L, Salcini A, Di Fiore P, et al. The epsins define a family of proteins that interact with components of the clathrin coat and contain a new protein module. J Biol Chem. 1999;274:33959-65 pubmed..The epsins define a new protein family implicated in membrane dynamics at the cell surface. ..
- Li C, Ullrich B, Zhang J, Anderson R, Brose N, Sudhof T. Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins. Nature. 1995;375:594-9 pubmed..The same C2 domains also bind syntaxin as a function of Ca2+ but the Ca(2+)-concentration dependence of Syt I, II and V (> 200 microM) differs from that of Syt III and VII (< 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS) ..
- Hussain N, Yamabhai M, Ramjaun A, Guy A, Baranes D, O Bryan J, et al. Splice variants of intersectin are components of the endocytic machinery in neurons and nonneuronal cells. J Biol Chem. 1999;274:15671-7 pubmed..These data suggest that the long and short forms of intersectin are components of the endocytic machinery in neurons and nonneuronal cells. ..
- Kariya K, Koyama S, Nakashima S, Oshiro T, Morinaka K, Kikuchi A. Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation. J Biol Chem. 2000;275:18399-406 pubmed..These results suggest that phosphorylation of Epsin in mitotic phase inhibits receptor-mediated endocytosis by disassembly of its complex with POB1 and alpha-adaptin. ..
- Lubben N, Sahlender D, Motley A, Lehner P, Benaroch P, Robinson M. HIV-1 Nef-induced down-regulation of MHC class I requires AP-1 and clathrin but not PACS-1 and is impeded by AP-2. Mol Biol Cell. 2007;18:3351-65 pubmed..We propose that depleting AP-2 potentiates Nef activity by altering the membrane composition and dynamics of endosomes and causing increased delivery of HLA-A2 to a prelysosomal compartment. ..
- Confalonieri S, Salcini A, Puri C, Tacchetti C, Di Fiore P. Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis. J Cell Biol. 2000;150:905-12 pubmed..Thus, tyrosine phosphorylation of Eps15 represents the first molecular determinant, other than those contained in the receptors themselves, which is involved in the differential regulation of constitutive vs. regulated endocytosis. ..
- Kamiguchi H, Long K, Pendergast M, Schaefer A, Rapoport I, Kirchhausen T, et al. The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via the clathrin-mediated pathway. J Neurosci. 1998;18:5311-21 pubmed..These results establish a mechanism by which L1 can be internalized from the cell surface and suggest that an active region of L1 endocytosis at the rear of growth cones is important in L1-dependent axon growth. ..
- Rotem Yehudar R, Galperin E, Horowitz M. Association of insulin-like growth factor 1 receptor with EHD1 and SNAP29. J Biol Chem. 2001;276:33054-60 pubmed
- Wollscheid H, Biancospino M, He F, Magistrati E, Molteni E, Lupia M, et al. Diverse functions of myosin VI elucidated by an isoform-specific Î±-helix domain. Nat Struct Mol Biol. 2016;23:300-308 pubmed publisher..Thus, the Î±2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles. ..
- Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, et al. The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. Hum Mol Genet. 2001;10:1807-17 pubmed
- van Delft S, Schumacher C, Hage W, Verkleij A, van Bergen en Henegouwen P. Association and colocalization of Eps15 with adaptor protein-2 and clathrin. J Cell Biol. 1997;136:811-21 pubmed..These findings suggest that Eps15 may play a critical role in the recruitment of active EGF receptors into coated pit regions before endocytosis of ligand-occupied EGF receptors. ..
- Crump C, Xiang Y, Thomas L, Gu F, Austin C, Tooze S, et al. PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J. 2001;20:2191-201 pubmed..These studies demonstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathogenesis. ..
- Santos da Silva E, Mulinge M, Perez Bercoff D. The frantic play of the concealed HIV envelope cytoplasmic tail. Retrovirology. 2013;10:54 pubmed publisher..It also considers the cellular and viral proteins that have been described to interact with the gp41-CT, with a particular focus on subtype-related polymorphisms. ..
- Campillos M, Garcia M, Valdivieso F, Vazquez J. Transcriptional activation by AP-2alpha is modulated by the oncogene DEK. Nucleic Acids Res. 2003;31:1571-5 pubmed..Finally, electrophoretic mobility shift assays suggested that DEK enhances the DNA-binding activity of AP-2alpha. Our data suggest a novel cellular function of DEK as a transcriptional co-activator. ..
- Metzler M, Legendre Guillemin V, Gan L, Chopra V, Kwok A, McPherson P, et al. HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2. J Biol Chem. 2001;276:39271-6 pubmed..Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery. ..
- Scorilas A, Levesque M, Ashworth L, Diamandis E. Cloning, physical mapping and structural characterization of the human alpha(A)-adaptin gene. Gene. 2002;289:191-9 pubmed..It is also ubiquitously expressed in tissues and in ZR-75-1 breast cancer cells and LNCaP prostate carcinoma cells as a smaller variant generated by splicing out of an exon encoding 22 amino acids in the hinge region of the protein. ..
- Kalthoff C, Groos S, Kohl R, Mahrhold S, Ungewickell E. Clint: a novel clathrin-binding ENTH-domain protein at the Golgi. Mol Biol Cell. 2002;13:4060-73 pubmed..Our results suggest that Clint might participate in the formation of clathrin-coated vesicles at the level of the trans-Golgi network and remains associated with the vesicles longer than clathrin and adaptors. ..
- Vendeville A, Rayne F, Bonhoure A, Bettache N, Montcourrier P, Beaumelle B. HIV-1 Tat enters T cells using coated pits before translocating from acidified endosomes and eliciting biological responses. Mol Biol Cell. 2004;15:2347-60 pubmed..Hence, Tat enters T cells essentially like diphtheria toxin, using clathrin-mediated endocytosis before low-pH-induced and Hsp90-assisted endosomal translocation. Cell responses are then induced from the cytosol. ..