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Protein

AP2-associated protein kinase 1

Gene

AAK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Stimulated by clathrin.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei74ATPPROSITE-ProRule annotation1
Active sitei176Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi52 – 60ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • AP-2 adaptor complex binding Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • Notch binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • endocytosis Source: UniProtKB-KW
  • positive regulation of Notch signaling pathway Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • protein phosphorylation Source: UniProtKB
  • protein stabilization Source: UniProtKB
  • regulation of clathrin-dependent endocytosis Source: UniProtKB
  • regulation of protein localization Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Endocytosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS03963-MONOMER.
ReactomeiR-HSA-8856825. Cargo recognition for clathrin-mediated endocytosis.
R-HSA-8856828. Clathrin-mediated endocytosis.
SignaLinkiQ2M2I8.
SIGNORiQ2M2I8.

Names & Taxonomyi

Protein namesi
Recommended name:
AP2-associated protein kinase 1 (EC:2.7.11.1)
Alternative name(s):
Adaptor-associated kinase 1
Gene namesi
Name:AAK1
Synonyms:KIAA1048
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:19679. AAK1.

Subcellular locationi

  • Cell membrane By similarity; Peripheral membrane protein By similarity
  • Membraneclathrin-coated pit By similarity

  • Note: Active when found in clathrin-coated pits at the plasma membrane. In neuronal cells, enriched at presynaptic terminals. In non-neuronal cells, enriched at leading edge of migrating cells (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Coated pit, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi74K → A: Inhibits autophosphorylation and phosphorylation of AP2M1. Does not affect NUMB localization. Does not interact with monoubiquitinated NOTCH1. 3 Publications1
Mutagenesisi176D → A: Inhibits autophosphorylation and phosphorylation of AP2M1. Does not affect NUMB localization. 2 Publications1
Mutagenesisi777 – 779DPF → AAA: Does not affect interaction with NOTCH1 but abolishes interaction with ESP15. 1 Publication3

Organism-specific databases

DisGeNETi22848.
OpenTargetsiENSG00000115977.
PharmGKBiPA134990616.

Chemistry databases

ChEMBLiCHEMBL3830.
GuidetoPHARMACOLOGYi1921.

Polymorphism and mutation databases

BioMutaiAAK1.
DMDMi300669613.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002505781 – 961AP2-associated protein kinase 1Add BLAST961

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei14PhosphoserineCombined sources1
Modified residuei234PhosphotyrosineCombined sources1
Modified residuei235PhosphoserineCombined sources1
Modified residuei354PhosphothreonineCombined sources1
Modified residuei389PhosphothreonineCombined sources1
Modified residuei391Omega-N-methylarginineBy similarity1
Modified residuei441PhosphothreonineCombined sources1
Modified residuei606PhosphothreonineCombined sources1
Modified residuei618PhosphoserineBy similarity1
Modified residuei620PhosphothreonineCombined sources1
Modified residuei623PhosphoserineCombined sources1
Modified residuei624PhosphoserineCombined sources1
Modified residuei637PhosphoserineCombined sources1
Modified residuei650PhosphoserineCombined sources1
Modified residuei653PhosphothreonineCombined sources1
Modified residuei687PhosphotyrosineCombined sources1
Modified residuei731PhosphoserineCombined sources1
Modified residuei846PhosphoserineBy similarity1
Modified residuei937PhosphoserineBy similarity1
Modified residuei938PhosphoserineBy similarity1

Post-translational modificationi

Autophosphorylated.By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein

Proteomic databases

EPDiQ2M2I8.
MaxQBiQ2M2I8.
PaxDbiQ2M2I8.
PeptideAtlasiQ2M2I8.
PRIDEiQ2M2I8.

PTM databases

iPTMnetiQ2M2I8.
PhosphoSitePlusiQ2M2I8.
SwissPalmiQ2M2I8.

Expressioni

Tissue specificityi

Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain.1 Publication

Gene expression databases

BgeeiENSG00000115977.
CleanExiHS_AAK1.
ExpressionAtlasiQ2M2I8. baseline and differential.
GenevisibleiQ2M2I8. HS.

Organism-specific databases

HPAiHPA017931.
HPA020289.

Interactioni

Subunit structurei

Interacts with alpha-adaptin, AP-2, clathrin, NUMB and EPS15 isoform 2. Interacts with membrane-bound activated NOTCH1 but not with the inactive full-length form of NOTCH1. Preferentially interacts with monoubiquitinated activated NOTCH1 compared to the non-ubiquitinated form.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ATP13A2Q9NQ112EBI-1383433,EBI-6308763

GO - Molecular functioni

  • AP-2 adaptor complex binding Source: UniProtKB
  • Notch binding Source: UniProtKB

Protein-protein interaction databases

BioGridi116520. 24 interactors.
IntActiQ2M2I8. 21 interactors.
STRINGi9606.ENSP00000386456.

Chemistry databases

BindingDBiQ2M2I8.

Structurei

Secondary structure

1961
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi30 – 34Combined sources5
Beta strandi38 – 41Combined sources4
Beta strandi44 – 53Combined sources10
Beta strandi56 – 65Combined sources10
Beta strandi70 – 78Combined sources9
Helixi81 – 97Combined sources17
Beta strandi106 – 118Combined sources13
Beta strandi120 – 127Combined sources8
Helixi134 – 139Combined sources6
Turni140 – 144Combined sources5
Helixi148 – 166Combined sources19
Beta strandi168 – 170Combined sources3
Helixi179 – 181Combined sources3
Beta strandi182 – 186Combined sources5
Beta strandi189 – 192Combined sources4
Helixi205 – 208Combined sources4
Helixi210 – 220Combined sources11
Helixi223 – 225Combined sources3
Helixi228 – 231Combined sources4
Helixi242 – 257Combined sources16
Turni261 – 264Combined sources4
Helixi266 – 271Combined sources6
Helixi284 – 293Combined sources10
Turni298 – 300Combined sources3
Helixi304 – 314Combined sources11
Helixi339 – 344Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4WSQX-ray1.95A/B29-345[»]
5L4QX-ray1.97A/B27-365[»]
ProteinModelPortaliQ2M2I8.
SMRiQ2M2I8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini46 – 315Protein kinasePROSITE-ProRule annotationAdd BLAST270

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi12 – 42Gly-richAdd BLAST31
Compositional biasi397 – 614Gln-richAdd BLAST218
Compositional biasi658 – 663Poly-Ala6

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG1989. Eukaryota.
ENOG410Y515. LUCA.
GeneTreeiENSGT00810000125451.
HOGENOMiHOG000232173.
HOVERGENiHBG080803.
InParanoidiQ2M2I8.
KOiK08853.
OMAiQAPIRQQ.
OrthoDBiEOG091G02KI.
PhylomeDBiQ2M2I8.
TreeFamiTF317300.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q2M2I8-1) [UniParc]FASTAAdd to basket
Also known as: AAK1L

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.

« Hide

        10         20         30         40         50
MKKFFDSRRE QGGSGLGSGS SGGGGSTSGL GSGYIGRVFG IGRQQVTVDE
60 70 80 90 100
VLAEGGFAIV FLVRTSNGMK CALKRMFVNN EHDLQVCKRE IQIMRDLSGH
110 120 130 140 150
KNIVGYIDSS INNVSSGDVW EVLILMDFCR GGQVVNLMNQ RLQTGFTENE
160 170 180 190 200
VLQIFCDTCE AVARLHQCKT PIIHRDLKVE NILLHDRGHY VLCDFGSATN
210 220 230 240 250
KFQNPQTEGV NAVEDEIKKY TTLSYRAPEM VNLYSGKIIT TKADIWALGC
260 270 280 290 300
LLYKLCYFTL PFGESQVAIC DGNFTIPDNS RYSQDMHCLI RYMLEPDPDK
310 320 330 340 350
RPDIYQVSYF SFKLLKKECP IPNVQNSPIP AKLPEPVKAS EAAAKKTQPK
360 370 380 390 400
ARLTDPIPTT ETSIAPRQRP KAGQTQPNPG ILPIQPALTP RKRATVQPPP
410 420 430 440 450
QAAGSSNQPG LLASVPQPKP QAPPSQPLPQ TQAKQPQAPP TPQQTPSTQA
460 470 480 490 500
QGLPAQAQAT PQHQQQLFLK QQQQQQQPPP AQQQPAGTFY QQQQAQTQQF
510 520 530 540 550
QAVHPATQKP AIAQFPVVSQ GGSQQQLMQN FYQQQQQQQQ QQQQQQLATA
560 570 580 590 600
LHQQQLMTQQ AALQQKPTMA AGQQPQPQPA AAPQPAPAQE PAIQAPVRQQ
610 620 630 640 650
PKVQTTPPPA VQGQKVGSLT PPSSPKTQRA GHRRILSDVT HSAVFGVPAS
660 670 680 690 700
KSTQLLQAAA AEASLNKSKS ATTTPSGSPR TSQQNVYNPS EGSTWNPFDD
710 720 730 740 750
DNFSKLTAEE LLNKDFAKLG EGKHPEKLGG SAESLIPGFQ STQGDAFATT
760 770 780 790 800
SFSAGTAEKR KGGQTVDSGL PLLSVSDPFI PLQVPDAPEK LIEGLKSPDT
810 820 830 840 850
SLLLPDLLPM TDPFGSTSDA VIEKADVAVE SLIPGLEPPV PQRLPSQTES
860 870 880 890 900
VTSNRTDSLT GEDSLLDCSL LSNPTTDLLE EFAPTAISAP VHKAAEDSNL
910 920 930 940 950
ISGFDVPEGS DKVAEDEFDP IPVLITKNPQ GGHSRNSSGS SESSLPNLAR
960
SLLLVDQLID L
Length:961
Mass (Da):103,885
Last modified:July 13, 2010 - v3
Checksum:i1FB44D0FDEF6CAD0
GO
Isoform 2 (identifier: Q2M2I8-2) [UniParc]FASTAAdd to basket
Also known as: AAK1S

The sequence of this isoform differs from the canonical sequence as follows:
     823-961: EKADVAVESL...LLLVDQLIDL → GKVIISVSSV...SPATPEAKAI

Show »
Length:863
Mass (Da):93,578
Checksum:i012198AEE90CC0E7
GO

Sequence cautioni

The sequence BAA83000 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04034859I → V.1 PublicationCorresponds to variant rs34535244dbSNPEnsembl.1
Natural variantiVAR_031129509K → Q.2 PublicationsCorresponds to variant rs6715776dbSNPEnsembl.1
Natural variantiVAR_040349533Q → H.1 Publication1
Natural variantiVAR_040350603V → A.1 PublicationCorresponds to variant rs56038532dbSNPEnsembl.1
Natural variantiVAR_040351694T → M.1 PublicationCorresponds to variant rs55889248dbSNPEnsembl.1
Natural variantiVAR_040352725P → T.1 PublicationCorresponds to variant rs35285785dbSNPEnsembl.1
Natural variantiVAR_040353771P → R.1 PublicationCorresponds to variant rs34422616dbSNPEnsembl.1
Natural variantiVAR_040354835G → D.1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_039459823 – 961EKADV…QLIDL → GKVIISVSSVMHDMCACFKN DKYLVNQSLGNSPATPEAKA I in isoform 2. 2 PublicationsAdd BLAST139

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB028971 mRNA. Translation: BAA83000.2. Different initiation.
AC092431 Genomic DNA. Translation: AAX88861.1.
AC079121 Genomic DNA. Translation: AAY14931.1.
AC136007 Genomic DNA. No translation available.
BC104842 mRNA. Translation: AAI04843.1.
BC111965 mRNA. Translation: AAI11966.1.
CCDSiCCDS1893.2. [Q2M2I8-1]
RefSeqiNP_055726.3. NM_014911.3.
UniGeneiHs.468878.

Genome annotation databases

EnsembliENST00000406297; ENSP00000385181; ENSG00000115977. [Q2M2I8-2]
ENST00000409085; ENSP00000386456; ENSG00000115977. [Q2M2I8-1]
GeneIDi22848.
KEGGihsa:22848.
UCSCiuc002sfp.3. human. [Q2M2I8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB028971 mRNA. Translation: BAA83000.2. Different initiation.
AC092431 Genomic DNA. Translation: AAX88861.1.
AC079121 Genomic DNA. Translation: AAY14931.1.
AC136007 Genomic DNA. No translation available.
BC104842 mRNA. Translation: AAI04843.1.
BC111965 mRNA. Translation: AAI11966.1.
CCDSiCCDS1893.2. [Q2M2I8-1]
RefSeqiNP_055726.3. NM_014911.3.
UniGeneiHs.468878.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4WSQX-ray1.95A/B29-345[»]
5L4QX-ray1.97A/B27-365[»]
ProteinModelPortaliQ2M2I8.
SMRiQ2M2I8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116520. 24 interactors.
IntActiQ2M2I8. 21 interactors.
STRINGi9606.ENSP00000386456.

Chemistry databases

BindingDBiQ2M2I8.
ChEMBLiCHEMBL3830.
GuidetoPHARMACOLOGYi1921.

PTM databases

iPTMnetiQ2M2I8.
PhosphoSitePlusiQ2M2I8.
SwissPalmiQ2M2I8.

Polymorphism and mutation databases

BioMutaiAAK1.
DMDMi300669613.

Proteomic databases

EPDiQ2M2I8.
MaxQBiQ2M2I8.
PaxDbiQ2M2I8.
PeptideAtlasiQ2M2I8.
PRIDEiQ2M2I8.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000406297; ENSP00000385181; ENSG00000115977. [Q2M2I8-2]
ENST00000409085; ENSP00000386456; ENSG00000115977. [Q2M2I8-1]
GeneIDi22848.
KEGGihsa:22848.
UCSCiuc002sfp.3. human. [Q2M2I8-1]

Organism-specific databases

CTDi22848.
DisGeNETi22848.
GeneCardsiAAK1.
H-InvDBHIX0161871.
HGNCiHGNC:19679. AAK1.
HPAiHPA017931.
HPA020289.
MIMi616405. gene.
neXtProtiNX_Q2M2I8.
OpenTargetsiENSG00000115977.
PharmGKBiPA134990616.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1989. Eukaryota.
ENOG410Y515. LUCA.
GeneTreeiENSGT00810000125451.
HOGENOMiHOG000232173.
HOVERGENiHBG080803.
InParanoidiQ2M2I8.
KOiK08853.
OMAiQAPIRQQ.
OrthoDBiEOG091G02KI.
PhylomeDBiQ2M2I8.
TreeFamiTF317300.

Enzyme and pathway databases

BioCyciZFISH:HS03963-MONOMER.
ReactomeiR-HSA-8856825. Cargo recognition for clathrin-mediated endocytosis.
R-HSA-8856828. Clathrin-mediated endocytosis.
SignaLinkiQ2M2I8.
SIGNORiQ2M2I8.

Miscellaneous databases

ChiTaRSiAAK1. human.
GeneWikiiAAK1.
GenomeRNAii22848.
PROiQ2M2I8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000115977.
CleanExiHS_AAK1.
ExpressionAtlasiQ2M2I8. baseline and differential.
GenevisibleiQ2M2I8. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiAAK1_HUMAN
AccessioniPrimary (citable) accession number: Q2M2I8
Secondary accession number(s): Q4ZFZ3, Q53RX6, Q9UPV4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 3, 2006
Last sequence update: July 13, 2010
Last modified: November 2, 2016
This is version 113 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.