8.A.203. The Adaptor Protein 4 Chaparone (AAGAB) Family The adaptor protein chaperone, AAGAB, stabilizes AP-4 complex subunits (Mattera et al. 2022). Adaptor protein 4 (AP-4) is a heterotetrameric complex composed of epsilon, beta4, mu4, and sigma4 subunits that mediates export of a subset of transmembrane cargos, including autophagy protein 9A (ATG9A), from the trans-Golgi network (TGN). AP-4 has received attention because mutations in any of its subunits cause a complicated form of hereditary spastic paraplegia referred to as "AP-4-deficiency syndrome." The identification of proteins that interact with AP-4 has revealed the mechanisms of AP-4-dependent cargo sorting and distribution within the cell. Mattera et al. 2022 reported that the alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34) binds to and stabilizes the AP-4 epsilon and sigma4 subunits, thus promoting complex assembly. The physiological importance of these interactions is underscored by the observation that AAGAB-knockout cells exhibit reduced levels of AP-4 subunits and accumulation of ATG9A at the TGN like those in cells with mutations in AP-4-subunit genes. Thus, AP-4 assembly is not spontaneous but AAGAB-assisted, further contributing to the understanding of an adaptor protein complex that is critically involved in development of the central nervous system (Mattera et al. 2022).
References:
Amores-Bonet, L., R. Kleene, T. Theis, and M. Schachner. (2022). Interactions between the Polysialylated Neural Cell Adhesion Molecule and the Transient Receptor Potential Canonical Channels 1, 4, and 5 Induce Entry of Ca into Neuron.s. Int J Mol Sci 23:.
Mattera, R., R. De Pace, and J.S. Bonifacino. (2022). The adaptor protein chaperone AAGAB stabilizes AP-4 complex subunits. Mol. Biol. Cell 33: ar109.
Pohler, E., O. Mamai, J. Hirst, M. Zamiri, H. Horn, T. Nomura, A.D. Irvine, B. Moran, N.J. Wilson, F.J. Smith, C.S. Goh, A. Sandilands, C. Cole, G.J. Barton, A.T. Evans, H. Shimizu, M. Akiyama, M. Suehiro, I. Konohana, M. Shboul, S. Teissier, L. Boussofara, M. Denguezli, A. Saad, M. Gribaa, P.J. Dopping-Hepenstal, J.A. McGrath, S.J. Brown, D.R. Goudie, B. Reversade, C.S. Munro, and W.H. McLean. (2012). Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat. Genet. 44: 1272-1276.
Examples:
TC#	Name	Organismal Type	Example
8.A.203.1.1	The adaptor protein 4 chaparone, AAGAB, of 315 aas and 1 - 3 N-terminal TMSs (residues 1 - 120). It may be involved in endocytic recycling of growth factor receptors such as EGFR (Pohler et al. 2012). The adaptor protein chaperone, AAGAB, stabilizes AP-4 complex subunits (Mattera et al. 2022). AP-4 is a heterotetrameric complex composed of epsilon, beta4, mu4, and sigma4 subunits that mediates export of a subset of transmembrane cargos, including autophagy protein 9A (ATG9A), from the trans-Golgi network (TGN). AP-4 has received attention because mutations in any of its subunits cause a complicated form of hereditary spastic paraplegia referred to as "AP-4-deficiency syndrome." The identification of proteins that interact with AP-4 has revealed the mechanisms of AP-4-dependent cargo sorting and distribution within the cell. Mattera et al. 2022 reported that the alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34) binds to and stabilizes the AP-4 epsilon and sigma4 subunits, thus promoting complex assembly. The physiological importance of these interactions is underscored by the observation that AAGAB-knockout cells exhibit reduced levels of AP-4 subunits and accumulation of ATG9A at the TGN like those in cells with mutations in AP-4-subunit genes. Thus, AP-4 assembly is not spontaneous but is AAGAB-assisted, further contributing to the understanding of an adaptor protein complex that is critically involved in development of the central nervous system (Mattera et al. 2022).		AAGAB of Homo sapiens