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First published online February 7, 2007
doi: 10.1242/10.1242/jcs.03365

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Neuronal and non-neuronal functions of the AP-3 sorting machinery

Karen Newell-Litwa^1,2, Eunju Seong^3,*, Margit Burmeister³ and Victor Faundez^1,4,

¹ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
² The Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, GA 30322, USA
³ Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
⁴ Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA

View larger version (31K): [in this window] [in a new window]   Fig. 1. Nomenclature and structure of AP-3 subunit isoforms. (A) AP-3 subunit genes and their corresponding gene products. The pattern of expression of each subunit is described as neuronal, corresponding to neurons and neuro-endocrine tissue, or ubiquitous, for subunits expressed in all cells including neuronal tissues. Mice carrying natural or engineered AP-3 subunit deficiencies are listed. (B) Proposed subunit composition of the neuronal and ubiquitous AP-3 isoforms. Both AP-3 complexes can carry either a 3A or a 3B subunit. (C) Adaptor complexes possess three defined domains. The ears correspond to the C-terminal domains of and 3. The trunk or core is composed of a protease-resistant core formed by fragments of 3 and as well as full-length µ3 and 3 subunits. The ears and trunk are connected by hinges.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Molecular interactions of the adaptor complex AP-3. The diagram depicts AP-3 subunits. is shown in red, 3 is shown in green, µ3 is shown in brown and 3 is shown in blue. Known interactions with a particular AP-3 subunit are indicated by a solid arrow. Interactions with AP-3 where the subunit is not known are depicted by a dashed arrow. These interactions correspond to PACS-1 (Crump et al., 2001), a casein kinase (Faundez and Kelly, 2000), BLOC-1 (Di Pietro et al., 2006) and inositol phospholipids (PI-Lipids). Vimentin (Styers et al., 2004), clathrin (Dell'Angelica et al., 1998) and the ataxia telangiectasia gene product (ATM) (Lim et al., 1998) directly associate with the 3 subunit. The subunit provides a platform sufficient to bind HIV Gag protein (Dong et al., 2005), protein G of the vesicular stomatitis virus (VSV-G) (Nishimura et al., 2002) or the R-(v)-SNARE VAMP7-TI (Martinez-Arca et al., 2003). Alternatively adaptin in a complex with 3 or 3 by itself binds di-leucine sorting motifs ([DE]xxx[LI]) (Janvier et al., 2003), AGAP1 (Nie et al., 2003), the Arf1 GTPase (Lefrancois et al., 2004), the ear domain (Lefrancois et al., 2004), and the insulin receptor substrate 1 (IRS1) (VanRenterghem et al., 1998). Tyrosine sorting motifs (Yxx) bind to the µ3 subunits (Ohno et al., 1995).

View larger version (28K): [in this window] [in a new window]   Fig. 3. AP-3 sorting mechanisms in neuronal cells. A neuron possesses neuronal and ubiquitous AP-3 complexes in the cell body (a) but only neuronal AP-3 in axons (b) and dendrites (c) (Seong et al., 2005). (A) Proposed functions of the neuronal and ubiquitous AP-3 in cell bodies. Both AP-3 forms reside in the same endosome. Neuronal AP-3 sorts proteins into the axon or a synaptic vesicle pathway. Ubiquitous AP-3 sorts proteins to the lysosomal pathway. Model A explains the changes in ZnT3 levels observed in Ap3b1–/– and Ap3b2–/– mice (Seong et al., 2005). In this model AP-3-sorted proteins, like ZnT3, are recognized by both AP-3 isoforms and therefore routed to either a synaptic vesicle-axonal or a lysosomal pathway. Thus, in the absence of one AP-3 isoform, membrane proteins are targeted to the other pathway. The amount of ZnT3 in synaptic vesicles is reduced in the absence of neuronal AP-3 (Ap3b2–/–) and ZnT3 is instead routed to lysosomes for degradation. Similarly, the amount of ZnT3 targeted to lysosomes is reduced in the absence of ubiquitous AP-3 (Ap3b1–/–) and it is then routed by the neuronal AP-3 (encoded by Ap3b2) to synaptic vesicles, thus triggering increased levels of ZnT3 in synaptic vesicles. Model B shows the proposed role of neuronal AP-3 in synaptic vesicle biogenesis in presynaptic terminals. AP-3 generates synaptic vesicles from presynaptic endosomes. This route is parallel to the AP-2 route, which generates synaptic vesicles from the plasma membrane. A role for AP-3 in sorting to dendrites (c) has not been documented yet.

View larger version (33K): [in this window] [in a new window]   Fig. 4. Models of BLOC-1–AP-3 sorting functions. (A,B) Two different vesicles, A and B, fuse with a target organelle (right). VAMP7-TI is present in vesicle A (blue cylinder). Its cognate Q-(t)-SNAREs (syntaxin 7, 8 and Vti1b; orange cylinders) are present in the target organelle. Model A depicts AP-3 and BLOC-1 complexes co-residing in vesicle A (Salazar et al., 2006). In this vesicle, BLOC-1 may regulate the recognition of specific cargoes, like the SNARE VAMP7-TI, either by bridging AP-3 and a selected membrane protein (interactions 2 and 3) or by stabilizing specific AP-3–cargo interactions (interactions 1 and 2). Interactions 1 (Martinez-Arca et al., 2003) and 2 have been documented (Di Pietro et al., 2006) and (G. Salazar and V.F., unpublished results). Interaction 3 is speculative. On the target membrane a tripartite Q-(t)-SNARE complex of syntaxin 7, syntaxin 8, and Vti1b is maintained by BLOC-1, independently of AP-3. Model B depicts the selective sorting of SNAREs or tissue-specific cargo into vesicle B by the BLOC-1 complex. Vesicle B represents a vesicle population distinct from vesicle A. Sorting into and/or biogenesis of vesicle B requires BLOC-1 but not AP-3 function. Model A and model B are non-exclusive. Either Model A alone or a combination of models A and B explain both the convergent sorting phenotypes of BLOC-1 and AP-3 deficiencies as well as the altered colocalization between syntaxins 7 and 8, which is unique to BLOC-1–mutant cells (Salazar et al., 2006).

View larger version (37K): [in this window] [in a new window]   Fig. 5. Subunit composition and molecular interactions of the BLOC-1 complex. (A) The model depicts the known subunit structure of the BLOC-1 complex. (B) The name of each subunit is denoted by the initial letter of the protein name. The diagram describes the intrinsic interactions between subunits of the BLOC-1 complex. For details see (Di Pietro and Dell'Angelica, 2005). (C) The diagram represents a partial list of interactions (solid lines), functional relationships (dashed line), or potential relationships (double-headed arrow with question mark) relevant to vesicle generation, fusion, and the pathogenesis of schizophrenia. A detailed list of interactions is described in (Di Pietro and Dell'Angelica, 2005).