Q9UKG1 (DP13A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
DCC-interacting protein 13-alpha
Short name=Dip13-alpha

Alternative name(s):
Adapter protein containing PH domain, PTB domain and leucine zipper motif 1

Gene names

Name:	APPL1
Synonyms:	APPL, DIP13A, KIAA1428

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	709 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Required for the regulation of cell proliferation in response to extracellular signals from an early endosomal compartment. Links Rab5 to nuclear signal transduction. Ref.1 Ref.6
Subunit structure	Binds RAB5A/Rab5 through an N-terminal domain. This interaction is essential for its recruitment to endosomal membranes as well as its role in cell proliferation. Binds DCC and the catalytic domain of the inactive form of AKT2 through its PID domain. Binds PIK3CA and subunits of the NuRD/MeCP1 complex. Interacts with OCRL and INPP5B. Ref.1 Ref.2 Ref.6 Ref.7 Ref.10 Ref.13 Ref.14
Subcellular location	Early endosome membrane; Peripheral membrane protein. Nucleus. Note: Early endosomal membrane-bound and nuclear. Translocated into the nucleus upon release from endosomal membranes following internalization of EGF. Ref.6 Ref.10
Tissue specificity	High levels in heart, ovary, pancreas and skeletal muscle. Ref.1
Domain	Overexpression of an N-terminal domain (residues 1-319) or a C-terminal region (residues 273-709) has a proapoptotic effect. Ref.6 The F&H motif, an approximately 12-13 amino-acid sequence centered around Phe and His residues, is essential for binding to OCRL and INPP5B (Ref.14).
Post-translational modification	Phosophorylation at Ser-410 by PKA severely impairs binding to OCRL.
Sequence similarities	Contains 1 PH domain. Contains 1 PID domain.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Endosome Membrane Nucleus
Coding sequence diversity	Polymorphism
Domain	Coiled coil
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Traceable author statement. Source: Reactome cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell proliferation Inferred from direct assay Ref.6. Source: UniProtKB insulin receptor signaling pathway Traceable author statement PubMed 17848569. Source: BHF-UCL regulation of apoptotic process Traceable author statement. Source: Reactome regulation of establishment of protein localization to plasma membrane Inferred from mutant phenotype PubMed 17848569. Source: BHF-UCL regulation of glucose import Inferred from mutant phenotype PubMed 17848569. Source: BHF-UCL
Cellular_component	cytosol Inferred from direct assay PubMed 17848569. Source: BHF-UCL early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endosome membrane Inferred from direct assay Ref.6. Source: UniProtKB nucleus Inferred from direct assay Ref.6. Source: UniProtKB vesicle membrane Inferred from direct assay PubMed 17848569. Source: BHF-UCL
Molecular_function	phospholipid binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ACTN2	P35609	2	EBI-741243,EBI-77797
ADIPOR1	Q96A54	6	EBI-741243,EBI-1632076
Adipor1	Q91VH1	3	EBI-741243,EBI-992398	From a different organism.
ADIPOR2	Q86V24	3	EBI-741243,EBI-1769445
DST	Q03001	3	EBI-741243,EBI-310758
DYSF	O75923	2	EBI-741243,EBI-2799016
SYNE2	Q8WXH0	3	EBI-741243,EBI-2372294

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 709

709

DCC-interacting protein 13-alpha

PRO_0000079985

Regions

Domain

277 – 375

99

PH

Domain

496 – 656

161

PID

Region

1 – 428

428

Required for RAB5A binding Ref.6

Coiled coil

215 – 259

45

Potential

Coiled coil

621 – 673

53

Potential

Motif

403 – 414

12

F&H

Amino acid modifications

Modified residue

399

1

Phosphothreonine Ref.9

Modified residue

401

1

Phosphoserine Ref.11

Modified residue

410

1

Phosphoserine; by PKA Ref.7

Natural variations

Natural variant

108

1

A → V.
Corresponds to variant rs4381906 [ dbSNP | Ensembl ].

VAR_050958

Natural variant

643

1

E → Q in a breast cancer sample; somatic mutation. Ref.15

VAR_035909

Natural variant

700

1

E → G.
Corresponds to variant rs11544593 [ dbSNP | Ensembl ].

VAR_050959

Secondary structure

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709

Helix Strand Turn

Details...

Helix

9 – 11

3

Turn

12 – 14

3

Helix

16 – 66

51

Helix

67 – 70

4

Helix

81 – 110

30

Helix

112 – 120

9

Helix

122 – 151

30

Beta strand

152 – 154

3

Helix

157 – 217

61

Helix

220 – 257

38

Helix

259 – 261

3

Beta strand

262 – 265

4

Turn

268 – 270

3

Beta strand

281 – 286

6

Beta strand

298 – 305

8

Beta strand

308 – 312

5

Beta strand

320 – 324

5

Beta strand

329 – 333

5

Beta strand

339 – 345

7

Beta strand

348 – 350

3

Helix

360 – 374

15

Beta strand

499 – 512

14

Helix

519 – 534

16

Beta strand

542 – 555

14

Turn

557 – 559

3

Beta strand

562 – 567

6

Helix

568 – 570

3

Beta strand

571 – 577

7

Beta strand

580 – 590

11

Beta strand

600 – 610

11

Helix

612 – 629

18

Sequences

	Sequence		Length	Mass (Da)
	Q9UKG1 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 4CABECFCF4BB110D	FASTA	709	79,663
	10 20 30 40 50 60 MPGIDKLPIE ETLEDSPQTR SLLGVFEEDA TAISNYMNQL YQAMHRIYDA QNELSAATHL 70 80 90 100 110 120 TSKLLKEYEK QRFPLGGDDE VMSSTLQQFS KVIDELSSCH AVLSTQLADA MMFPITQFKE 130 140 150 160 170 180 RDLKEILTLK EVFQIASNDH DAAINRYSRL SKKRENDKVK YEVTEDVYTS RKKQHQTMMH 190 200 210 220 230 240 YFCALNTLQY KKKIALLEPL LGYMQAQISF FKMGSENLNE QLEEFLANIG TSVQNVRREM 250 260 270 280 290 300 DSDIETMQQT IEDLEVASDP LYVPDPDPTK FPVNRNLTRK AGYLNARNKT GLVSSTWDRQ 310 320 330 340 350 360 FYFTQGGNLM SQARGDVAGG LAMDIDNCSV MAVDCEDRRY CFQITSFDGK KSSILQAESK 370 380 390 400 410 420 KDHEEWICTI NNISKQIYLS ENPEETAARV NQSALEAVTP SPSFQQRHES LRPAAGQSRP 430 440 450 460 470 480 PTARTSSSGS LGSESTNLAA LSLDSLVAPD TPIQFDIISP VCEDQPGQAK AFGQGGRRTN 490 500 510 520 530 540 PFGESGGSTK SETEDSILHQ LFIVRFLGSM EVKSDDHPDV VYETMRQILA ARAIHNIFRM 550 560 570 580 590 600 TESHLLVTCD CLKLIDPQTQ VTRLTFPLPC VVLYATHQEN KRLFGFVLRT SSGRSESNLS 610 620 630 640 650 660 SVCYIFESNN EGEKICDSVG LAKQIALHAE LDRRASEKQK EIERVKEKQQ KELNKQKQIE 670 680 690 700 KDLEEQSRLI AASSRPNQAS SEGQFVVLSS SQSEESDLGE GGKKRESEA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2." Mitsuuchi Y., Johnson S.W., Sonoda G., Tanno S., Golemis E.A., Testa J.R. Oncogene 18:4891-4898(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH AKT2 AND PIK3CA.
[2]	"Mediation of the DCC apoptotic signal by DIP13 alpha." Liu J., Yao F., Wu R., Morgan M., Thorburn A., Finley R.L. Jr., Chen Y.Q. J. Biol. Chem. 277:26281-26285(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH DCC.
[3]	"Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O. DNA Res. 7:65-73(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[4]	"Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones." Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T. DNA Res. 9:99-106(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SEQUENCE REVISION.
[5]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Testis.
[6]	"APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment." Miaczynska M., Christoforidis S., Giner A., Shevchenko A., Uttenweiler-Joseph S., Habermann B., Wilm M., Parton R.G., Zerial M. Cell 116:445-456(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAB5A AND NURD/MECP1 COMPLEX, IDENTIFICATION BY MASS SPECTROMETRY.
[7]	"A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway." Erdmann K.S., Mao Y., McCrea H.J., Zoncu R., Lee S., Paradise S., Modregger J., Biemesderfer D., Toomre D., De Camilli P. Dev. Cell 13:377-390(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH OCRL, F&H MOTIF, PHOSPHORYLATION AT SER-410.
[8]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Embryonic kidney.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-399, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1." Swan L.E., Tomasini L., Pirruccello M., Lunardi J., De Camilli P. Proc. Natl. Acad. Sci. U.S.A. 107:3511-3516(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH OCRL, SUBCELLULAR LOCATION.
[11]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-401, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway." Noakes C.J., Lee G., Lowe M. Mol. Biol. Cell 22:606-623(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH OCRL.
[14]	"Recognition of the F&H motif by the Lowe syndrome protein OCRL." Pirruccello M., Swan L.E., Folta-Stogniew E., De Camilli P. Nat. Struct. Mol. Biol. 18:789-795(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH OCRL, F&H MOTIF.
[15]	"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., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] GLN-643.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF169797 mRNA. Translation: AAF04012.1.
AF424738 mRNA. Translation: AAL17835.1.
AB037849 mRNA. Translation: BAA92666.2.
BC028599 mRNA. Translation: AAH28599.1.

IPI

IPI00015836.

RefSeq

NP_036228.1. NM_012096.2.

UniGene

Hs.476415.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EJ8	X-ray	1.84	A/B	492-644	[»]
2ELA	X-ray	2.00	A/B	493-646	[»]
2ELB	X-ray	2.60	A	1-376	[»]
2Q12	X-ray	1.79	A	5-265	[»]
2Q13	X-ray	2.05	A	5-385	[»]
2Z0N	X-ray	1.95	A	1-275	[»]
2Z0O	X-ray	2.58	A	1-385	[»]

ProteinModelPortal

Q9UKG1.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29322N.

IntAct

Q9UKG1. 40 interactions.

MINT

MINT-1177965.

STRING

9606.ENSP00000288266.

PTM databases

PhosphoSite

Q9UKG1.

Polymorphism databases

DMDM

61213025.

Proteomic databases

PaxDb

Q9UKG1.

PeptideAtlas

Q9UKG1.

PRIDE

Q9UKG1.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000288266; ENSP00000288266; ENSG00000157500.

GeneID

26060.

KEGG

hsa:26060.

UCSC

uc003dio.3. human.

Organism-specific databases

CTD

26060.

GeneCards

GC03P057237.

HGNC

HGNC:24035. APPL1.

HPA

HPA011138.

MIM

604299. gene.

neXtProt

NX_Q9UKG1.

PharmGKB

PA162376755.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG69757.

HOGENOM

HOG000285988.

HOVERGEN

HBG051394.

InParanoid

Q9UKG1.

KO

K08733.

OMA

SDVETMQ.

OrthoDB

EOG4PVNZ2.

PhylomeDB

Q9UKG1.

Enzyme and pathway databases

Pathway_Interaction_DB

ar_pathway. Coregulation of Androgen receptor activity.

Reactome

REACT_578. Apoptosis.

SignaLink

Q9UKG1.

Gene expression databases

ArrayExpress

Q9UKG1.

Bgee

Q9UKG1.

CleanEx

HS_APPL1.

Genevestigator

Q9UKG1.

GermOnline

ENSG00000157500. Homo sapiens.

Family and domain databases

Gene3D

1.20.1270.60. 1 hit.
2.30.29.30. 2 hits.

InterPro

IPR027267. AH/BAR-dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR006020. PTyr_interaction_dom.
[Graphical view]

Pfam

PF00640. PID. 1 hit.
[Graphical view]

SMART

SM00233. PH. 1 hit.
[Graphical view]

PROSITE

PS50003. PH_DOMAIN. 1 hit.
PS01179. PID. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

APPL1. human.

EvolutionaryTrace

Q9UKG1.

GenomeRNAi

26060.

NextBio

47954.

SOURCE

Search...

Entry information

Entry name

DP13A_HUMAN

Accession

Primary (citable) accession number: Q9UKG1
Secondary accession number(s): Q9P2B9

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	May 1, 2000
Last modified:	May 29, 2013
This is version 108 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.