Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

AP-3

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_548

Historical Background

The cytoplasm of all eukaryotic cells is organized into a complex set of membrane-bound organelles with defined protein and lipid composition. Proteins and lipids of the endocytic and exocytic pathways are transported between these compartments by small vesicles and tubules which pinch off from one compartment and fuse with another and so deliver their contents. The budding of vesicles and tubules from membranes is driven by the recruitment of coat protein complexes from the cytoplasm. Coat complexes have two main functions in this process: First, they select cargo proteins to be packaged into the vesicle, and second, they recruit accessory proteins that help deform the membrane into a bud and bind machinery required for vesicle fission.

In mammalian cells, there are five related adaptor protein (AP) complexes (AP-1 through 5) (Hirst et al. 2011). Each complex is localized to a specific post-Golgi compartment and is required for the transport of a defined set of cargo molecules (Fig. 1 and Table 3). The AP-1 complex is localized to the trans-Golgi network and tubular endosomes and plays a role in the trafficking of proteins between these compartments such as the mannose 6-phosphate receptors and the R-SNARE, VAMP4. The AP-2 adaptor complex is localized to the plasma membrane and is required for the internalization of cell surface receptors such as the transferrin receptor and the low-density lipoprotein receptor. The AP-3 complex is localized to tubular endosomes and is required for the trafficking of lysosomal proteins such as LAMPI and LIMPII. The  AP-4 complex is localized to the TGN and endosomes and is involved in the trafficking of the amyloid precursor protein. The AP-5 complex is localized to late endosomes. However, what cargo proteins it traffics is not known.
AP-3, Fig. 1

AP complexes are localized to post-Golgi membranes. (a) Diagram showing the primary localization of adaptor complexes within a generic mammalian cell. Arrows indicate transport routes between compartments. TGN trans-Golgi network. (b) A mouse fibroblast stained for the AP-1 (γ) and AP-3 (δ) adaptor complexes. Scale bar 30 μm

AP-3, Table 3

AP-3 cargo proteins

Proposed AP-3 cargo

Interaction motif on cargo

Interaction domain on AP-3

Method used to show interaction

Observed phenotype of cargo protein when interaction with AP-3 is perturbed

LAMPI

GYQTI

μ3

Biocore and yeast two-hybrid

Increased cell surface trafficking in the absence of AP-3

LAMPII

GYEQF

μ3*

 

Increased cell surface trafficking in the absence of AP-3

LIMPII

ERAPLI

δ/σ3

Biocore and yeast two-hybrid

Increased cell surface trafficking in the absence of AP-3

CD63

GYEVM

μ3

Yeast two-hybrid

Increased cell surface trafficking in the absence of AP-3

CD164/Endolyn

NYHTL

μ3

Yeast two-hybrid

Increased cell surface trafficking in the absence of AP-3

Tyrosinase

EERQPLL

δ/σ3

Biocore, yeast two-hybrid, and biochemical pull down

Altered trafficking in AP-3-deficient melanocytes

ZnT3

C-terminus

?

co-IP

Significant changes in localization and levels in mocha brains

Battenin/CLN3

EEEAESAARQPLI

δ/σ3*

Biochemical pull down

Altered trafficking in mocha and pearl fibroblasts

OCA2

ENTPLL

δ/σ3

Yeast two-hybrid and biochemical pull down

Altered trafficking of transiently expressed OCA2 that can no longer interact with AP-3

HIV-GAG

Matrix fragment

δ-hinge domain

Yeast two-hybrid and biochemical pull down

Altered trafficking to multivesicular bodies when interaction with AP-3 is perturbed

CD1b

SYGNI

μ3

Biocore and yeast two-hybrid

Increased cell surface trafficking and loss of lysosomal localization in the absence of AP-3

VAMP7

VAMP7 longin domain

δ-hinge domain

Yeast two-hybrid and co-IP

Altered trafficking in AP-3-deficient fibroblasts

PI4KIIa

ERQPLL

δ/σ3*

Biochemical pull down and co-IP

Altered trafficking in mocha fibroblasts and changes in distribution in mocha brains

Elastase

YPDA

μ3

Yeast two-hybrid

Altered trafficking/expression in AP-3-deficient neutrophils

High-affinity choline transporter/CHT

?

?

 

Significant changes in localization and levels in mocha brains

CB1 cannabinoid receptor

?

?

co-IP

Change in cellular distribution when AP-3 depleted

Chloride Channel/CLC3

?

?

 

Altered trafficking in mocha fibroblasts and changes in distribution in mocha brains

Chloride Channel/CLC-7

N-terminus (EAAPLL) C-terminus?

δ/σ3*

Biochemical pull down

Increased trafficking over the plasma membrane when sorting signal mutated

Niemann-Pick Type C1/NPC1

?

?

 

Increased cell surface trafficking in the absence of AP-3

Niemann-Pick Type C2/NPC2

?

?

 

Decreased levels in the media in AP-3-deficient fibroblasts

IP immunoprecipitation

*Based on the motif found in the cargo protein it is likely to interact with the indicated subunits of the AP-3 complex. However, this has not been formally shown for this cargo

Adaptor protein complexes are heterotetramers consisting of a related set of subunits. The AP-1 complex consists of γ, β1, μ1, and σ1; AP-2 of α, β2, μ2, and σ2; AP-3 of δ, β3, μ3, and σ3; AP-4 of ε, β4, μ4, and σ4; and AP-5 of ζ, β5, μ5, and σ5. Each subunit within the adaptor complex plays a specific role in the process of vesicle budding, for example, the μ subunits bind cargo proteins; the β subunits bind clathrin in the case of β1-3, the structural component of the vesicle required for membrane deformation; and the α/γ type subunits bind accessory proteins that regulate the process.

The first AP complexes to be characterized were AP-1 and AP-2 as they are major components of clathrin-coated vesicles. The next AP complex to be identified was AP-3. The first subunits of the AP-3 complex were isolated by expression cloning in the early 1990s and the subsequent subunits of the complex were identified through their sequence homology to subunits of the AP-1 and AP-2 complexes, reviewed in (Odorizzi et al. 1998).

The first insights into the function of the AP-3 complex came through the discovery that garnet fruit flies are missing the δ subunit of the AP-3 complex. Garnet flies have reduced pigmentation in their eyes suggesting that the AP-3 complex is involved in the biogenesis of pigment granules, which are a lysosome-related organelle. In support of this hypothesis it was then discovered that the mouse coat color mutants mocha and pearl have disruption in the β3A and δ subunits respectively, and that people with Hermansky–Pudlak syndrome type 2 are missing the β3A subunit, reviewed in (Odorizzi et al. 1998; Badolato and Parolini 2007). People with HPS type 2 have reduced pigmentation (skin, hair, and eyes), defects in blood clotting, and susceptibility to recurrent infections. The majority of these phenotypes can be explained by defects in melanocytes, platelet dense granules, and lytic granules which are lysosome-related organelles (Badolato and Parolini 2007). In addition to defects in specalized compartments there is also increased trafficking of lysosomal integral membrane proteins over the cell surface in cells isolated from mice or patients lacking functional AP-3 complexes (Table 3) (Dell’Angelica et al. 1999).

This entry will primarily focus on outlining what is currently known regarding the function and regulation of the mammalian AP-3 complex in generic cell types. For detailed reviews regarding the biology of the AP-3 complex in non-vertebrate systems and in specalized cell types such as melanosomes and neurons, see (Raposo and Marks 2007; Dell’Angelica 2009; Danglot and Galli 2007).

AP-3 Complex Subunit Composition, Expression, and Function

The AP-3 complex is a heterotetramer of approximately 320 kDa. The complex consists of two large subunits δ (130 kDa), β3 (120 kDa), a medium subunit μ3 (47 kDa), and a small subunit σ3 (21 kDa) (see Table 1 and Fig. 2) (Simpson et al. 1997). Once the individual subunits of the AP complexes are synthesized they assemble very rapidly into a complex so the levels of individual subunits in the cytoplasm are negligible under normal conditions. Deletion or disruption of either of the large subunits leads to disassembly and degradation of the other subunits of the complex.
AP-3, Table 1

AP-3 complex subunits

Subunit name

Official NCBI symbol

Gene ID

Splice isoforms (aa)

Expression

Function within complex

δ

AP3D1

8943

2 (1153 and 1112aa)

Ubiquitous

Binding membranes and accessory proteins?

β3A

AP3B1

8546

1 (1094aa)

Ubiquitous

Binding accessory proteins

β3B

AP3B2

8120

1 (1101aa)

Neuronal and pancreatic tissue

Binding accessory proteins

μ3A

AP3M1

26985

2 (418)

Ubiquitous

Binding cargo, Yxx∅

μ3B

AP3M2

10947

2 (418)

Neuronal and pancreatic tissue

Binding cargo, Yxx∅

σ3A

AP3S1

1176

1 (193aa)

Ubiquitous

Binding cargo, [D/E]xxxL[L/I]

σ3B

AP3S2

10239

1 (193aa)

Ubiquitous

Binding cargo, [D/E]xxxL[L/I]

Information shown for human AP-3 subunits

aa amino acids

AP-3, Fig. 2

Schematic of the AP-3 adaptor complex. Structure of the AP-3 complex based on its homology to the AP-2 adaptor complex. Diagram shows subunit interactions and functional domains

Tissue-Specific Expression

There are two isoforms of the β3, μ3, and σ3 subunits. All tissues express δ, β3A, μ3A, σ3A, and σ3B, and neuronal and pancreatic tissues express β3B and μ3B in addition (see Table 1). It has been proposed that there are ubiquitous (δ, β3A, μ3A, σ3A/B) and neuronal (δ, β3B, μ3B, σ3A/B) forms of the AP-3 complex. This hypothesis is partially supported by phenotypic analysis of mice either lacking both complexes (mocha mice) or just the neuronal (μ3B) complex, reviewed in Danglot and Galli (2007).

Large Subunits

The large subunits (also known as adaptins) of the AP-3 complex have three domains: a folded trunk domain of approximately 70 kDa, a flexible linker domain of around 20 kDa, and a folded appendage domain of 30 kDa (Fig. 2). The trunk domains of δ and β3 consist of α solenoid fold and interact with the σ3 and μ3 subunits respectively. The trunk domain of the δ subunit may also be involved in membrane binding as the comparable region on the α subunit of AP-2 binds phosphatidylinositol 4,5-bisphosphate (PIP2) (Jackson et al. 2010).

Very little is known about the appendage domains of β3 and δ adaptin. Based on homology they are predicted to have a bi-lobal structure. The appendage domains of α (AP-2) and γ (AP-1) adaptin bind accessory proteins that regulate vesicle budding and fission. At present no appendage domain binding proteins have been identified for AP-3. However, it is likely that they exist because AP-3 complexes lacking the β3 appendage domain are unable to traffic lysosomal proteins efficiently, and mocha 2J mice that lack the δ appendage domain have a coat color phenotype. Interestingly, the δ ear does not have the conserved platform required for binding accessory proteins found on the α subunit indicating that the δ subunit must bind accessory proteins in an alternate manner.

Medium Subunits

The main function of the μ3 subunit is to bind cargo molecules that contain tyrosine-based sorting signals (see section “AP-3 Cargo Proteins” and Table 2) (Ohno et al. 1998). The μ3 subunit is predicted to have two folded domains connected via a short linker. The N-terminal domain has a longin type fold and interacts with the other subunits of the complex, and the C-terminal domain binds cargo molecules (see section “AP-3 Cargo Proteins”). μ3A and B have been shown to bind similar cargo molecules using yeast two-hybrid analysis.
AP-3, Table 2

AP-3 interacting proteins

Interacting protein

Interaction motif/domain on binding protein

Interaction domain on AP-3

Method used to show interaction

Clathrin

β-propeller of clathrin’s N-terminal domain

Flexible linker domains of β3A (LLDLD) and β3B (LLDLE)

Biochemical “pull down”

ARF1

Switch 1 and switch 2

δ/σ3 subcomplex

Yeast two-hybrid and co-IP

KIF3A

C-terminus (601–702)

β3A hinge (676–902)

Yeast two-hybrid and biochemical pull down

AGAP1

PH domain

δ/σ3 subcomplex

Yeast two-hybrid

BLOC-1 (Dysbindin subunit)

Dysbindin

μ3 or β3B?

Biochemical “pull downs”

A representative list of mammalian AP-3 interacting proteins which have had their binding site mapped

Small Subunits

The main known function of the σ3 subunit is to bind cargo molecules that contain dileucine type motifs (see section “AP-3 Cargo Proteins” and Table 2) (Janvier et al. 2003). The σ3 subunits are predicted to be globular and have a longin type fold. Based on the structure of the σ2–dileucine interaction is predicted that σ3 binds dileucine signals using a conserved hydrophobic pocket on its surface (Jackson et al. 2010). σ3A and B are both ubiquitously expressed and at present it is unclear why there are two isoforms. It is possible that having both isoforms may increase the repertoire of cargo molecules the AP-3 complex can bind, or there may be as yet unidentified interacting partners. In addition to binding cargo molecules, σ3A/B have also been shown to be capable of interacting with the appendage domain of the δ subunit, and this interaction may regulate AP-3 recruitment onto membranes (see section “Regulation of the AP-3 Complex”).

AP-3 Complex Interacting Proteins

Over the past 15 years, many approaches have been used to identify AP-3 complex interacting partners. These include yeast two-hybrid screens, proteomic studies on immuno-isolated AP-3 complexes, vesicles, and AP-3-coated liposomes. Thus, the number of proposed AP-3 interacting proteins has increased steadily. However, the numbers are relatively low compared to the AP-1 and 2 complexes suggesting that there are more to be discovered. It must be noted that for many of the AP-3 interacting partners it is still not known what domains and/or subunits of the AP-3 complex are involved in mediating the interaction. In the following section, I have outlined some of the known AP-3 interacting proteins. This list is not exhaustive but focuses only on the interacting partners who have had their binding to AP-3 mapped.

Clathrin

The AP-3 complex has been shown to bind clathrin in vitro and partially colocalize with clathrin in vivo. The β3A/B subunits have a clathrin-binding motif called a clathrin box (L∅x∅[D/Ε]), where ∅ is a bulky hydrophobic residue and x is any residue (Dell’Angelica et al. 1998). Mutation of this motif abolishes AP-3’s interaction with clathrin. Surprisingly, AP-3 is not enriched in purified clathrin-coated vesicles and does not require clathrin to function. Mutation of the clathrin-binding box in AP-3 does not drastically affect lysosomal protein trafficking, and depletion of clathrin from an AP-3 based in vitro budding assay did not inhibit AP-3 budding. Furthermore, a significant fraction of AP-3 positive vesicles and tubules do not label for clathrin. Thus, the role of clathrin in AP-3 function still remains uncertain. Not all adaptor complexes require clathrin to function. For example, AP-4 and AP-5 do not contain clathrin-binding boxes and do not colocalize with clathrin in vivo and yeast AP-3 does not require clathrin for function. At present it is unclear why certain AP complexes require clathrin as a structural scaffold to help generate a vesicle and others do not. It is possible that other proteins may be performing the same function as clathrin. In yeast, it has been proposed that Vps41 may be playing this role for AP-3, and for AP-5 SPG11 may be performing this function.

ARF1 and AGAP1

ARF1 is required for AP-3 recruitment to membranes. The binding domain of ARF1 has been mapped to the trunk domain of the δ/σ3 subcomplex. This interaction has been shown to be modulated by the interaction of the δ-appendage domain with the C-terminal domain of the σ3 subunit (Lefrancois et al. 2004). The ARF1 GAP, AGAP1 also binds to AP-3 (Nie et al. 2003) (see section “Regulation of the AP-3 Complex”).

KIF3A

The motor protein KIF3A has been shown to bind to the hinge region of β3A and disruption of this interaction causes a defect in HIV budding (Azevedo et al. 2009). KIF3A is a component of the plus end directed motor Kinesin-2. Kinesin-2 has been shown to play a role in the transport of endosome-derived vesicles.

BLOC-1 Complex

The AP-3 complex interacts with biogenesis of lysosome-related organelles complex-1 (BLOC-1) (Di Pietro et al. 2006). BLOC-1 consists of 8 known subunits: pallidin, cappuccino, muted, snapin, dysbindin, BLOS1, BLOS2, and BLOS3. Disruption of BLOC-1 function leads to defects in the biogenesis of lysosome-related organelles and increased cell surface trafficking of lysosomal proteins. The molecular function of this complex is still unknown. It is likely that the interaction between BLOC-1 and AP-3 occurs through the dysbindin subunit of the complex. However, it remains unclear which subunit or subunits of the AP-3 complex mediate this interaction as μ3 and β3 have both been proposed to bind dysbindin.

AP-3 Cargo Proteins

One of the main functions of an AP complex is to select cargo molecules into forming vesicle (Bonifacino and Traub 2003). Loss of AP-3 complex function leads to increased cell surface trafficking of lysosomal proteins as well as defects in the targeting of certain cargoes to lysosome and lysosome-related organelles (Fig. 3). The AP-3 complex, like the other well-characterized adaptor complexes (AP-1/2), is capable of binding two types of linear motifs found in the cytoplasmic tails of cargo molecules. Studies using yeast two-hybrid assays have shown that the C-terminal domain of the μ3 subunit binds tyrosine-based motifs Yxx∅ (where ∅ is a bulk hydrophobic residue and x is variable but tends to be hydrophilic in nature) (Ohno et al. 1998). Studies using yeast three-hybrid assays have shown that di-leucine-based motifs [D/E]xxxL[L/I] (where x is any residue) bind a hemi-complex formed from the δ/σ3 subunits (Janvier et al. 2003). The binding affinities of both types of motifs for AP complexes are relatively weak and in the μM KD range.
AP-3, Fig. 3

Loss of AP-3 causes increased trafficking of lysosomal proteins over the cell surface. (a) Mocha fibroblasts were transfected with the δ subunit of the AP-3 complex and allowed to internalize antibodies to the lysosomal protein LAMPI for 30 min at 37 °C. The cells were fixed and stained for δ adaptin and LAMPI. Scale bar 30 μm. Asterisk marks cell not expressing δ adaptin. (b) Mocha (mh) fibroblasts were transfected with the δ subunit of the AP-3 complex and the cell surface levels of LAMPI determined using flow cytometry

The AP-3 complex can also bind cargo that does not contain either tyrosine or di-leucine-based motifs. For example, the endosomal R-SNARE  VAMP7 and the HIV-GAG protein have shown to interact with the hinge domain of the δ subunit of the complex, and disruption of this interaction alters the trafficking of both proteins. For a detailed list of proposed AP-3 cargo proteins, see Table 3. It must be stated that for many of these proteins it has still to be confirmed whether there is a direct interaction between these proteins and the AP-3 complex. Thus, it is possible that changes observed in their trafficking in AP-3-deficient cells may be indirect.

Regulation of the AP-3 Complex

For AP complexes to function they must continually cycle on and off membranes. This cycle is regulated through a combination of weak μM–KD interactions involving small GTPases, lipids, and cargo proteins. This cycle has been best elucidated for the AP-2 complex (Jackson et al. 2010). The AP-2 complex is initially recruited onto membranes via its interaction with PIP2. This interaction leads to a conformational switch in the complex that allows the μ2 and σ2 subunits to bind cargo proteins thereby increasing the affinity/avidity of the interaction. In addition to the conformational switch there is also further regulation where the linker domain of the μ2 subunit is phosphorylated, which greatly increases the affinity of the μ2 subunit for binding of cargo molecules. At present very little is known about the regulation of the AP-3 complex. However, it is clear that ARF1 plays a major role in this process.

ARF1, GEFs, and GAPs

The main GTPase-regulating AP-3 membrane association is ARF1 (Table 2). ARF1 is a small GTPase that cycles between an active GTP and an inactive GDP form. In the active form, ARF1 recruits AP-3 onto membranes. Disruption of the GTP cycle using the fungal metabolite Brefeldin A causes ARF1 to accumulate in the GDP locked form and causes AP-3 to dissociate from membranes. Yeast two-hybrid mapping experiments have indicated that ARF1 binds to the trunk domain of the δ/σ3 hemicomplex. Further mapping indicated that the C-terminal domain of the σ3 subunit is also important for this interaction (Lefrancois et al. 2004). Interestingly, this C-terminal domain has also been shown to bind the δ appendage domain using three-hybrid mapping and so potentially provides a mechanism for regulating membrane binding. In support of this hypothesis, overexpression of the appendage domain of δ adaptin caused AP-3 to become cytosolic and increase the trafficking of lysosomal membrane proteins over the plasma membrane.

The activity of ARF1 is regulated by GTP exchange factors and GTPase-activating proteins. It has been shown that ARF1 GEF BIG1 is recruited on to synthetic liposomes enriched in AP-3 and that depletion of BIG1 using siRNA causes the loss of AP-3 from membranes and an increase in the trafficking of lysosomal membrane proteins over the cell surface. The ARF1 GAP, AGAP1 has been shown to bind to AP-3 using the yeast three-hybrid assay (see Table 2). Overexpression of AGAP1 causes AP-3 to dissociate from membranes, and depletion of AGAP1 by siRNA makes AP-3 Brefeldin A insensitive (Nie et al. 2003). In addition, the GAP ARAP1 binds liposomes enriched in AP-3 complexes, and its depletion affects AP-3 binding to membranes (Baust et al. 2008). However, it is not known if ARAP1 directly interacts with AP-3.

PIP Binding

As mentioned earlier it has been shown that AP-2 recruitment to membranes is regulated by PIP2 binding. The binding site on the trunk domain of the α subunit of AP-2 has been mapped and it is clear that the δ trunk domain of AP-3 also has a basic patch, although not as basic. However, it is not known whether phosphoinositides bind this patch. A good candidate is phosphatidylinositol 3-phosphate (PI3P) as studies using synthetic liposomes have shown that AP-3 preferentially binds to membrane enriched in PI3P. In addition, depletion of the enzyme PI-3KIIIC3, which generates PI3P, affects the recruitment of AP-3 to membranes and increases the trafficking of LAMPI over the plasma membrane (Baust et al. 2008). However, PI3P may not be the only lipid involved in AP-3 recruitment as PI-4KIIα is enriched in AP-3-derived vesicles and it can directly bind AP-3 via its dileucine motif (Craige et al. 2008). Depletion of PI-4KIIα blocks the recruitment of AP-3 to membranes, and like the loss of PI-3KIIIC3 also causes a LAMP1 trafficking defect. At present it is not known whether the binding of AP-3 to phosphoinositides might cause a conformational switch in the complex which allows it to bind cargo. In the case of AP-1, it is thought that this switch may be primarily regulated by the binding of ARF1 and not phosphoinositides.

Phosphorylation

The only subunits of the AP-3 complex to be significantly phosphorylated are β3A and β3B (Faundez and Kelly 2000). These subunits are phosphorylated on serine residues present in acidic patches in their flexible linker regions. In β3A approximately 31% of the hinge residues are acidic and a further 26% are serine residues. The linker regions of β3A and β3B contain many potential casein kinase I and II sites. It has been shown that a casein kinase 1α activity co-purifies with the AP-3 complexes isolated from cytosol. Inhibition of casein kinase activity reduces AP-3-dependent synaptic vesicle budding in vitro. However, it is unclear whether there are other substrates for casein kinase in the budding assay. KIF3A has recently been identified as a β3A linker domain interacting protein and its binding has been shown to be regulated by the phosphorylation state of the hinge domain (Table 2). In vitro assays using yeast extract have suggested that the acidic patches in the β3 linker domain may be substrates for IP7-mediated pyrophosphorylation and the levels of pyrophosphorylation may regulate the interaction (Azevedo et al. 2009).

Summary

Since its discovery over 15 years ago a substantial amount of progress has been made in elucidating the function of the AP-3 complex. It is now known that the complex is involved in the biogenesis of lysosome-related organelles, and loss of the complex in humans causes Hermansky–Pudlak syndrome type 2. The number of cargo molecules the complex traffics and the interacting proteins it binds is steadily increasing. Progress has been made in understanding how the complex is recruited onto membranes. However, several major questions/challenges remain. How many trafficking routes is the AP-3 complex involved in? Does AP-3 have any appendage domain binding proteins? What role does BLOC-1 have in AP-3 function? Why does AP-3 bind clathrin but not require it for its function? How do μ3B and β3B give AP-3 neuronal-specific functions when they appear to bind the same proteins as μ3A and β3A? How do AP-3-binding partners regulate its function? How are all these interactions coordinated within the cell?

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Cambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK