9.B.278. The Organellar-targeting Adaptor Protein Complex (O-APC) Family 

Selective transport of transmembrane proteins to different intracellular compartments often involves the recognition of sorting signals in the cytosolic domains of the proteins by components of membrane coats. Some of these coats have as their key components a family of heterotetrameric adaptor protein (AP) complexes named AP-1 through AP-5. AP complexes play important roles in all cells, but their functions are most critical in neurons because of the extreme compartmental complexity of these cells. Accordingly, various diseases caused by mutations in AP subunit genes exhibit a range of neurological abnormalities as their most salient features. Guardia et al. 2018 discussed the properties of the different AP complexes, with a focus on their roles in neuronal physiology and pathology. AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A (Davies et al. 2018). Three transmembrane cargo proteins, ATG9A, SERINC1 and SERINC3, and two AP-4 accessory proteins, RUSC1 and RUSC2 are involved.  Davies et al. 2018 demonstrated that AP-4 deficiency causes mis-sorting of ATG9A in diverse cell types as well as dysregulation of autophagy. RUSC2 facilitates the transport of AP-4-derived, ATG9A-positive vesicles from the trans-Golgi network to the cell periphery. These vesicles cluster in close association with autophagosomes, suggesting they are the 'ATG9A reservoir' required for autophagosome biogenesis.



Davies, A.K., D.N. Itzhak, J.R. Edgar, T.L. Archuleta, J. Hirst, L.P. Jackson, M.S. Robinson, and G.H.H. Borner. (2018). AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nat Commun 9: 3958.

Guardia, C.M., R. De Pace, R. Mattera, and J.S. Bonifacino. (2018). Neuron.al functions of adaptor complexes involved in protein sorting. Curr Opin Neurobiol 51: 103-110. [Epub: Ahead of Print]

He, X., F. Li, W.P. Chang, and J. Tang. (2005). GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J. Biol. Chem. 280: 11696-11703.

Kang, E.L., A.N. Cameron, F. Piazza, K.R. Walker, and G. Tesco. (2010). Ubiquitin regulates GGA3-mediated degradation of BACE1. J. Biol. Chem. 285: 24108-24119.

Lau, A.W. and M.M. Chou. (2008). The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway. J Cell Sci 121: 4008-4017.

Marcello, E., C. Saraceno, S. Musardo, H. Vara, A.G. de la Fuente, S. Pelucchi, D. Di Marino, B. Borroni, A. Tramontano, I. Pérez-Otaño, A. Padovani, M. Giustetto, F. Gardoni, and M. Di Luca. (2013). Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. J Clin Invest 123: 2523-2538.

Mattera, R., C.D. Williamson, X. Ren, and J.S. Bonifacino. (2020). The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Mol. Biol. Cell 31: 963-979.

Nakatsu, F. and H. Ohno. (2003). Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct Funct 28: 419-429.

Owen, D.J., B.M. Collins, and P.R. Evans. (2004). Adaptors for clathrin coats: structure and function. Annu. Rev. Cell Dev. Biol. 20: 153-191.

Paing, M.M., C.A. Johnston, D.P. Siderovski, and J. Trejo. (2006). Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol. Cell Biol. 26: 3231-3242.

Partlow, E.A., R.W. Baker, G.M. Beacham, J.S. Chappie, A.E. Leschziner, and G. Hollopeter. (2019). A structural mechanism for phosphorylation-dependent inactivation of the AP2 complex. Elife 8:.

Puertollano, R., P.A. Randazzo, J.F. Presley, L.M. Hartnell, and J.S. Bonifacino. (2001). The GGAs promote ARF-dependent recruitment of clathrin to the TGN. Cell 105: 93-102.

Roach, T.G., H.K.M. Lång, W. Xiong, S.J. Ryhänen, and D.G.S. Capelluto. (2021). Protein Trafficking or Cell Signaling: A Dilemma for the Adaptor Protein TOM1. Front Cell Dev Biol 9: 643769.

Tesco, G., Y.H. Koh, E.L. Kang, A.N. Cameron, S. Das, M. Sena-Esteves, M. Hiltunen, S.H. Yang, Z. Zhong, Y. Shen, J.W. Simpkins, and R.E. Tanzi. (2007). Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron. 54: 721-737.

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Zhang, M., J.E. Davis, C. Li, J. Gao, W. Huang, N.A. Lambert, A.V. Terry, Jr, and G. Wu. (2016). GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export. Mol. Cell Biol. 36: 1152-1163.


TC#NameOrganismal TypeExample

The Adaptor Protein Complex, AP1 with subunits β1 (AP1B1, 949 aas), γ1 (AP1G1, 822 aas), μ1 (AP1M1; 423 aas) and σ1 (AP1S1, 158 aas).  Subunits of clathrin-associated adaptor protein complex 1 form a complex that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules (Guardia et al. 2018). These complexes therefore play a role in protein insertion into organellar membranes.  There is one isoform of β1, two of γ1, two of
μ1, and three of σ1. Only one iso-form of each is included here.  Although there are 5 such complexes in humans (AP-1 - 5), and many eukaryotic organisms have one of more of them, only AP1 of humans is tabulated in TCDB (Guardia et al. 2018). Parts of subunits β1 and γ1 are homologous, and parts of subunits μ1 and σ1 show significant sequence similarity, suggestiong homology. Subunits β and γ are homologous as are subunits sigma and mu.

AP1 complex of Homo sapiens


Golgi/endosome-localizing monomeric clathrin adaptors, GGAs.  GGA1 is of 639 aas and is a gamma-adaptin ear-containing, ADP ribosylation factor [Arf]-binding protein. The family is  ubiquitously expressed Arf-dependent monomeric clathrin adaptor proteins that are conserved from yeast to humans. Mammals have three GGAs (GGA1-3) that work not only at the trans-Golgi network, but also in endosomes to sort transmembrane cargo proteins such as mannose 6-phosphate receptors, sortilin, beta-site amyloid precursor protein cleaving enzyme 1, and epidermal growth factor receptor (Uemura and Waguri 2019).

GGA1 of Homo sapiens


GGA3, a paralog of GGA1 (TC# 9.B.278.1.2) of 723 aas with 50% identity with GGA1 (Uemura and Waguri 2019).  It plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes and mediates the ARF-dependent recruitment of clathrin to the TGN.  It binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (DXXLL) motif (PubMed Puertollano et al. 2001). It also mediates export of the GPCR receptor ADRA2B to the cell surface (Zhang et al. 2016). It is involved in BACE1 transport and sorting as well as regulation of BACE1 protein levels (Tesco et al. 2007, He et al. 2005, Kang et al. 2010). Finally it regulates retrograde transport of BACE1 from endosomes to the trans-Golgi network via interaction through the VHS motif, dependent of BACE1 phosphorylation (He et al. 2005). The N-terminal 200 residue region resembles (e-6) that of ESCRT-III family protein P38753 in TC# 3.A.31.1.1.

GGA3 of Homo sapiens


AP2 clathrin adaptor complex, AP2A1, A2, B1, M1, S1.  Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways and are vesicle coat components that appear to be involved in cargo selection and vesicle formation (Nakatsu and Ohno 2003). AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome (Owen et al. 2004). The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components; AP2 directly regulates PAR1 trafficking, (Paing et al. 2006). Clathrin-associated adaptor protein (AP) complexes, which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes, are considered to be the major clathrin adaptors contributing to CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis and seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway (Lau and Chou 2008). During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10 (Marcello et al. 2013). The AP-2 mu subunit binds to transmembrane cargo proteins and recognizes the Y-X-X-Phi motifs. The surface region interacting with the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at 'Tyr-156' in membrane-associated AP-2 (Partlow et al. 2019). Subunits α1, α2 and β appear to be homologous.

AP2 clathrin adaptor protein complex of Homo sapiens
AP2A1 (α-1)
AP2A2 (α-2)
AP2B1 (β)
AP2M1 (μ)
AP2S1 (σ)


AP4 complex with 5 subunits, alpha-1, beta-1, epsilon-1, mu-1 and Tepsin. The FTS-Hook-FHIP (FHF) complex interacts With the AP-4 complex to mediate perinuclear distribution of AP-4 and its cargo, ATG9A (Mattera et al. 2020).

AP4 complex of Homo sapiens

Sigma-1 or AP4S1 of 144 aas (Q9Y587)
Beta-1 or AP4B1 of 737 aas (Q9Y6B7)
Mu-1 or AP4M1 of 453 aas (O00189)
Epsilon-1 or AP4E1 of 1137 aas (Q9UPM8)
Tepsin or Enthd2 or 525 aas and 1 TMS (Q96N21)


The target of Myp protein 1, TOM1 of 492 aas and    TMSs. Lysosomal degradation of ubiquitinated transmembrane protein receptors (cargo) relies on the function of Endosomal Sorting Complex Required for Transport (ESCRT; TC# #.A.31) protein complexes. The ESCRT machinery is comprised of five unique oligomeric complexes with distinct functions. The target of Myb1 (TOM1) is an ESCRT protein involved in the initial steps of endosomal cargo sorting. To exert its function, TOM1 associates with ubiquitin moieties on the cargo via its VHS and GAT domains. Several ESCRT proteins, including TOLLIP, Endofin, and Hrs, have been reported to form a complex with TOM1 at early endosomal membrane surfaces, which may potentiate the role of TOM1 in cargo sorting. TOM1 is involved in other physiological processes, including autophagy, immune responses, and neuroinflammation, which crosstalk with its endosomal cargo sorting function. Alteration of TOM1 function has emerged as a phosphoinositide-dependent survival mechanism for bacterial infections and cancer progression. Based on current knowledge of TOM1-dependent cellular processes, Roach et al. 2021 reviewed how TOM1 functions in coordination with an array of protein partners under physiological and pathological scenarios.