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Protein

AP2-associated protein kinase 1

Gene

AAK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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.

Activity 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

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processEndocytosis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

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

EuPathDBiHostDB:ENSG00000115977.18
HGNCiHGNC:19679 AAK1
MIMi616405 gene
neXtProtiNX_Q2M2I8

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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

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
ProteomicsDBi61355
61356 [Q2M2I8-2]

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 Expressed in 237 organ(s), highest expression level in occipital lobe
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

Protein-protein interaction databases

BioGridi116520, 39 interactors
IntActiQ2M2I8, 22 interactors
MINTiQ2M2I8
STRINGi9606.ENSP00000386456

Chemistry databases

BindingDBiQ2M2I8

Structurei

Secondary structure

1961
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

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

Phylogenomic databases

eggNOGiKOG1989 Eukaryota
ENOG410Y515 LUCA
GeneTreeiENSGT00880000137958
HOGENOMiHOG000232173
HOVERGENiHBG080803
InParanoidiQ2M2I8
KOiK08853
OMAiCPVQNVQ
OrthoDBiEOG091G02KI
PhylomeDBiQ2M2I8
TreeFamiTF317300

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9PG46E9PG46_HUMAN
AP2-associated protein kinase 1
AAK1
674Annotation score:
A0A096LNZ0A0A096LNZ0_HUMAN
AP2-associated protein kinase 1
AAK1
339Annotation score:
A0A096LP25A0A096LP25_HUMAN
AP2-associated protein kinase 1
AAK1
511Annotation score:
A0A096LP60A0A096LP60_HUMAN
AP2-associated protein kinase 1
AAK1
99Annotation score:

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 → V1 PublicationCorresponds to variant dbSNP:rs34535244Ensembl.1
Natural variantiVAR_031129509K → Q2 PublicationsCorresponds to variant dbSNP:rs6715776Ensembl.1
Natural variantiVAR_040349533Q → H1 Publication1
Natural variantiVAR_040350603V → A1 PublicationCorresponds to variant dbSNP:rs56038532Ensembl.1
Natural variantiVAR_040351694T → M1 PublicationCorresponds to variant dbSNP:rs55889248Ensembl.1
Natural variantiVAR_040352725P → T1 PublicationCorresponds to variant dbSNP:rs35285785Ensembl.1
Natural variantiVAR_040353771P → R1 PublicationCorresponds to variant dbSNP:rs34422616Ensembl.1
Natural variantiVAR_040354835G → D1 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

Similar proteinsi

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[»]
5TE0X-ray1.90A27-365[»]
ProteinModelPortaliQ2M2I8
SMRiQ2M2I8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116520, 39 interactors
IntActiQ2M2I8, 22 interactors
MINTiQ2M2I8
STRINGi9606.ENSP00000386456

Chemistry databases

BindingDBiQ2M2I8
ChEMBLiCHEMBL3830

PTM databases

iPTMnetiQ2M2I8
PhosphoSitePlusiQ2M2I8
SwissPalmiQ2M2I8

Polymorphism and mutation databases

BioMutaiAAK1
DMDMi300669613

Proteomic databases

EPDiQ2M2I8
MaxQBiQ2M2I8
PaxDbiQ2M2I8
PeptideAtlasiQ2M2I8
PRIDEiQ2M2I8
ProteomicsDBi61355
61356 [Q2M2I8-2]

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
EuPathDBiHostDB:ENSG00000115977.18
GeneCardsiAAK1
H-InvDBiHIX0161871
HGNCiHGNC:19679 AAK1
HPAiHPA017931
HPA020289
MIMi616405 gene
neXtProtiNX_Q2M2I8
OpenTargetsiENSG00000115977
PharmGKBiPA134990616
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1989 Eukaryota
ENOG410Y515 LUCA
GeneTreeiENSGT00880000137958
HOGENOMiHOG000232173
HOVERGENiHBG080803
InParanoidiQ2M2I8
KOiK08853
OMAiCPVQNVQ
OrthoDBiEOG091G02KI
PhylomeDBiQ2M2I8
TreeFamiTF317300

Enzyme and pathway databases

ReactomeiR-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828 Clathrin-mediated endocytosis
SignaLinkiQ2M2I8
SIGNORiQ2M2I8

Miscellaneous databases

ChiTaRSiAAK1 human
GeneWikiiAAK1
GenomeRNAii22848
PROiPR:Q2M2I8
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000115977 Expressed in 237 organ(s), highest expression level in occipital lobe
CleanExiHS_AAK1
ExpressionAtlasiQ2M2I8 baseline and differential
GenevisibleiQ2M2I8 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiAAK1_HUMAN
AccessioniPrimary (citable) accession number: Q2M2I8
Secondary accession number(s): Q4ZFZ3, Q53RX6, Q9UPV4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 3, 2006
Last sequence update: July 13, 2010
Last modified: November 7, 2018
This is version 130 of the entry and version 3 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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