Reviewed, UniProtKB/Swiss-Prot Q9NZ52 (GGA3_HUMAN)

Names and origin

Protein names

Recommended name:
    ADP-ribosylation factor-binding protein GGA3
Alternative name(s):
    Golgi-localized, gamma ear-containing, ARF-binding protein 3

Gene names

Name:	GGA3
Synonyms:	KIAA0154

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	723 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (AC-LL) motif.
Subunit structure	Monomeric. Interacts with SORT1, SORL1, LRP3, GGA binding partner (GGABP) and P200 By similarity. Interacts with GGA1 and GGA2. Binds to clathrin and activated ARFs. Binds RABEP1 and RABGEF1. Interacts with the membrane proteins M6PR/CD-MPR, IGF2R/CI-MPR and BACE1 and the accessory proteins AP1GBP1, EPN4, NECAP1, NECAP2 and AFTPH/aftiphilin. Interacts with TSG101 and UBC.
Subcellular location	Golgi apparatus › trans-Golgi network membrane; Peripheral membrane protein. Endosome membrane; Peripheral membrane protein.
Tissue specificity	Ubiquitously expressed.
Domain	The VHS domain functions as a recognition module for sorting signals composed of an acidic cluster followed by two leucines (AC-LL motif). The GAT domain is responsible for interaction with ARF-GTP, UBC and RABEP1. Required for recruitment to the TGN it prevents ARF-GTP hydrolysis. The unstructured hinge region contains clathrin-binding and an autoinhibitory (AC-LL) motifs. The GAE domain binds accessory proteins regulating GGAs function.
Post-translational modification	Phosphorylated by CK2 and dephosphorylated by PP2A By similarity. Phosphorylation of GGA3 allows the internal AC-LL motif to bind the VHS domain and to inhibit the recognition of cargo signals. Ubiquitinated.
Sequence similarities	Belongs to the GGA protein family. Contains 1 GAE domain. Contains 1 GAT domain. Contains 1 VHS domain.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Endosome Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	intracellular protein transport Ref.2 Non-traceable author statement. Source: UniProtKB vesicle-mediated transport Inferred from electronic annotation. Source: InterPro
Cellular component	clathrin adaptor complex Inferred from electronic annotation. Source: InterPro endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell trans-Golgi network Ref.2 Inferred from direct assay. Source: UniProtKB
Molecular function	ADP-ribosylation factor binding Ref.2 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RABEP1	Q15276	1	EBI-447404,EBI-447043
RABGEF1	O18973	1	EBI-447404,EBI-447376	From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: Q9NZ52-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: Q9NZ52-2)

The sequence of this isoform differs from the canonical sequence as follows:
     68-100: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 723

723

ADP-ribosylation factor-binding protein GGA3

PRO_0000212684

Regions

Domain

16 – 146

131

VHS

Domain

171 – 298

128

GAT

Domain

594 – 715

122

GAE

Region

1 – 313

313

Binds to ARF1 (in long isoform)

Region

299 – 593

295

Unstructured hinge

Motif

391 – 395

5

Autoinhibitory

Compositional bias

357 – 360

4

Poly-Pro

Compositional bias

453 – 457

5

Poly-Ser

Compositional bias

624 – 629

6

Poly-Val

Natural variations

Alternative sequence

68 – 100

33

Missing in isoform Short.

VSP_001745

Natural variant

574

1

P → L in a breast cancer sample; somatic mutation.

VAR_036524

Experimental info

Mutagenesis

194

1

N → A: Loss of interaction with ARF1 and Golgi localization

Mutagenesis

199

1

S → P: Loss of interaction with ARF1 and Golgi localization

Mutagenesis

217

1

T → P: Loss of interaction with ARF1 and Golgi localization

Mutagenesis

247

1

L → P: Loss of UBC-binding and ubiquitination

Mutagenesis

258

1

K → M: No effect. Confers an affinity to RABEP1 identical to GGA1; when associated with N-283

Mutagenesis

262

1

L → S: Loss of UBC-binding and ubiquitination

Mutagenesis

276

1

L → A: Loss of UBC-binding and ubiquitination

Mutagenesis

276

1

L → S: Loss of UBC-binding and ubiquitination

Mutagenesis

280

1

L → R: Loss of UBC-binding and ubiquitination

Mutagenesis

283

1

S → N: Can bind RABEP1. Confers an affinity to RABEP1 identical to GGA1; when associated with M-258

Mutagenesis

284

1

D → G: Loss of UBC-binding and ubiquitination

Mutagenesis

293

1

Y → H: Loss of UBC-binding and ubiquitination

Mutagenesis

391 – 395

5

DEELL → AAAAA: Increased binding to IGF2R

Sequence conflict

448

1

Q → K in AAH70044. Ref.4

Secondary structure

1

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723

Helix Strand Turn

Details...

Helix

4 – 17

14

Helix

26 – 38

13

Helix

42 – 54

13

Helix

59 – 75

17

Helix

77 – 84

8

Helix

87 – 97

11

Turn

99 – 101

3

Helix

102 – 105

4

Helix

108 – 124

17

Helix

129 – 140

12

Helix

218 – 231

14

Turn

232 – 234

3

Turn

237 – 239

3

Helix

242 – 267

26

Helix

276 – 290

15

Helix

292 – 295

4

Turn

296 – 298

3

Helix

588 – 590

3

Beta strand

599 – 604

6

Beta strand

607 – 616

10

Beta strand

624 – 633

10

Beta strand

635 – 637

3

Beta strand

639 – 647

9

Beta strand

652 – 656

5

Beta strand

675 – 683

9

Beta strand

692 – 700

9

Beta strand

703 – 711

9

Helix

717 – 719

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified October 1, 2000. Version 1. Checksum: 4F80D6032239168C	FASTA	723	78,315
	10 20 30 40 50 60 MAEAEGESLE SWLNKATNPS NRQEDWEYII GFCDQINKEL EGPQIAVRLL AHKIQSPQEW 70 80 90 100 110 120 EALQALTVLE ACMKNCGRRF HNEVGKFRFL NELIKVVSPK YLGDRVSEKV KTKVIELLYS 130 140 150 160 170 180 WTMALPEEAK IKDAYHMLKR QGIVQSDPPI PVDRTLIPSP PPRPKNPVFD DEEKSKLLAK 190 200 210 220 230 240 LLKSKNPDDL QEANKLIKSM VKEDEARIQK VTKRLHTLEE VNNNVRLLSE MLLHYSQEDS 250 260 270 280 290 300 SDGDRELMKE LFDQCENKRR TLFKLASETE DNDNSLGDIL QASDNLSRVI NSYKTIIEGQ 310 320 330 340 350 360 VINGEVATLT LPDSEGNSQC SNQGTLIDLA ELDTTNSLSS VLAPAPTPPS SGIPILPPPP 370 380 390 400 410 420 QASGPPRSRS SSQAEATLGP SSTSNALSWL DEELLCLGLA DPAPNVPPKE SAGNSQWHLL 430 440 450 460 470 480 QREQSDLDFF SPRPGTAACG ASDAPLLQPS APSSSSSQAP LPPPFPAPVV PASVPAPSAG 490 500 510 520 530 540 SSLFSTGVAP ALAPKVEPAV PGHHGLALGN SALHHLDALD QLLEEAKVTS GLVKPTTSPL 550 560 570 580 590 600 IPTTTPARPL LPFSTGPGSP LFQPLSFQSQ GSPPKGPELS LASIHVPLES IKPSSALPVT 610 620 630 640 650 660 AYDKNGFRIL FHFAKECPPG RPDVLVVVVS MLNTAPLPVK SIVLQAAVPK SMKVKLQPPS 670 680 690 700 710 720 GTELSPFSPI QPPAAITQVM LLANPLKEKV RLRYKLTFAL GEQLSTEVGE VDQFPPVEQW GNL
	Isoform Short [UniParc]. Checksum: E3A1C841AB3966C8		690	74,470
	10 20 30 40 50 60 MAEAEGESLE SWLNKATNPS NRQEDWEYII GFCDQINKEL EGPQIAVRLL AHKIQSPQEW 70 80 90 100 110 120 EALQALTYLG DRVSEKVKTK VIELLYSWTM ALPEEAKIKD AYHMLKRQGI VQSDPPIPVD 130 140 150 160 170 180 RTLIPSPPPR PKNPVFDDEE KSKLLAKLLK SKNPDDLQEA NKLIKSMVKE DEARIQKVTK 190 200 210 220 230 240 RLHTLEEVNN NVRLLSEMLL HYSQEDSSDG DRELMKELFD QCENKRRTLF KLASETEDND 250 260 270 280 290 300 NSLGDILQAS DNLSRVINSY KTIIEGQVIN GEVATLTLPD SEGNSQCSNQ GTLIDLAELD 310 320 330 340 350 360 TTNSLSSVLA PAPTPPSSGI PILPPPPQAS GPPRSRSSSQ AEATLGPSST SNALSWLDEE 370 380 390 400 410 420 LLCLGLADPA PNVPPKESAG NSQWHLLQRE QSDLDFFSPR PGTAACGASD APLLQPSAPS 430 440 450 460 470 480 SSSSQAPLPP PFPAPVVPAS VPAPSAGSSL FSTGVAPALA PKVEPAVPGH HGLALGNSAL 490 500 510 520 530 540 HHLDALDQLL EEAKVTSGLV KPTTSPLIPT TTPARPLLPF STGPGSPLFQ PLSFQSQGSP 550 560 570 580 590 600 PKGPELSLAS IHVPLESIKP SSALPVTAYD KNGFRILFHF AKECPPGRPD VLVVVVSMLN 610 620 630 640 650 660 TAPLPVKSIV LQAAVPKSMK VKLQPPSGTE LSPFSPIQPP AAITQVMLLA NPLKEKVRLR 670 680 690 YKLTFALGEQ LSTEVGEVDQ FPPVEQWGNL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"GGAs: a family of ADP ribosylation factor-binding proteins related to adaptors and associated with the Golgi complex." Dell'Angelica E.C., Puertollano R., Mullins C., Aguilar R.C., Vargas J.D., Hartnell L.M., Bonifacino J.S. J. Cell Biol. 149:81-94(2000) [PubMed: 10747089] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT). Tissue: Heart.
[2]	"A family of ADP-ribosylation factor effectors that can alter transport through the trans-Golgi." Boman A.L., Zhang C.-J., Zhu X., Kahn R.A. Mol. Biol. Cell 11:1241-1255(2000) [PubMed: 10749927] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
[3]	"Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1." Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N. DNA Res. 2:167-174(1995) [PubMed: 8590280] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT). Tissue: Bone marrow.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT). Tissue: Brain.
[5]	"Adaptor gamma ear homology domain conserved in gamma-adaptin and GGA proteins that interact with gamma-synergin." Takatsu H., Yoshino K., Nakayama K. Biochem. Biophys. Res. Commun. 271:719-725(2000) [PubMed: 10814529] [Abstract] Cited for: INTERACTION WITH AP1GBP1.
[6]	"The GGAs promote ARF-dependent recruitment of clathrin to the TGN." Puertollano R., Randazzo P.A., Presley J.F., Hartnell L.M., Bonifacino J.S. Cell 105:93-102(2001) [PubMed: 11301005] [Abstract] Cited for: MUTAGENESIS OF ASN-194; SER-199 AND THR-217, INTERACTION WITH ARF1 AND CLATHRIN, FUNCTION.
[7]	"Sorting of mannose 6-phosphate receptors mediated by the GGAs." Puertollano R., Aguilar R.C., Gorshkova I., Crouch R.J., Bonifacino J.S. Science 292:1712-1716(2001) [PubMed: 11387475] [Abstract] Cited for: INTERACTION WITH M6PR AND IGF2R.
[8]	"GGA proteins associate with Golgi membranes through interaction between their GGAH domains and ADP-ribosylation factors." Takatsu H., Yoshino K., Toda K., Nakayama K. Biochem. J. 365:369-378(2002) [PubMed: 11950392] [Abstract] Cited for: INTERACTION WITH ARF1; ARF5 AND ARF6.
[9]	"Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics." Wasiak S., Legendre-Guillemin V., Puertollano R., Blondeau F., Girard M., de Heuvel E., Boismenu D., Bell A.W., Bonifacino J.S., McPherson P.S. J. Cell Biol. 158:855-862(2002) [PubMed: 12213833] [Abstract] Cited for: INTERACTION WITH EPN4.
[10]	"Autoinhibition of the ligand-binding site of GGA1/3 VHS domains by an internal acidic cluster-dileucine motif." Doray B., Bruns K., Ghosh P., Kornfeld S.A. Proc. Natl. Acad. Sci. U.S.A. 99:8072-8077(2002) [PubMed: 12060753] [Abstract] Cited for: MUTAGENESIS OF 391-ASP--LEU-395, INTERACTION WITH IGF2R, AUTOINHIBITION.
[11]	"Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins." He X., Zhu G., Koelsch G., Rodgers K.K., Zhang X.C., Tang J. Biochemistry 42:12174-12180(2003) [PubMed: 14567678] [Abstract] Cited for: INTERACTION WITH BACE1.
[12]	"Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex." Mattera R., Arighi C.N., Lodge R., Zerial M., Bonifacino J.S. EMBO J. 22:78-88(2003) [PubMed: 12505986] [Abstract] Cited for: INTERACTION WITH RABEP1 AND RABGEF1.
[13]	"Mammalian GGAs act together to sort mannose 6-phosphate receptors." Ghosh P., Griffith J., Geuze H.J., Kornfeld S. J. Cell Biol. 163:755-766(2003) [PubMed: 14638859] [Abstract] Cited for: INTERACTION WITH GGA1 AND GGA2.
[14]	"GAT (GGA and Tom1) domain responsible for ubiquitin binding and ubiquitination." Shiba Y., Katoh Y., Shiba T., Yoshino K., Takatsu H., Kobayashi H., Shin H.-W., Wakatsuki S., Nakayama K. J. Biol. Chem. 279:7105-7111(2004) [PubMed: 14660606] [Abstract] Cited for: MUTAGENESIS OF LEU-247; LEU-262; LEU-276; LEU-280; ASP-284 AND TYR-293, INTERACTION WITH UBC, UBIQUITINATION.
[15]	"Definition of the consensus motif recognized by gamma-adaptin ear domains." Mattera R., Ritter B., Sidhu S.S., McPherson P.S., Bonifacino J.S. J. Biol. Chem. 279:8018-8028(2004) [PubMed: 14665628] [Abstract] Cited for: INTERACTION WITH NECAP1; NECAP2 AND AFTPH.
[16]	"The trihelical bundle subdomain of the GGA proteins interacts with multiple partners through overlapping but distinct sites." Mattera R., Puertollano R., Smith W.J., Bonifacino J.S. J. Biol. Chem. 279:31409-31418(2004) [PubMed: 15143060] [Abstract] Cited for: MUTAGENESIS OF LYS-258 AND SER-283, INTERACTION WITH RABEP1.
[17]	"Interactions of GGA3 with the ubiquitin sorting machinery." Puertollano R., Bonifacino J.S. Nat. Cell Biol. 6:244-251(2004) [PubMed: 15039775] [Abstract] Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-276, INTERACTION WITH UBC AND TSG101.
[18]	"Phosphoregulation of sorting signal-VHS domain interactions by a direct electrostatic mechanism." Kato Y., Misra S., Puertollano R., Hurley J.H., Bonifacino J.S. Nat. Struct. Biol. 9:532-536(2002) [PubMed: 12032548] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-166.
[19]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J.,