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Protein

AP2-associated protein kinase 1

Gene

Aak1

Organism
Mus musculus (Mouse)
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 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Stimulated by clathrin.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei74 – 741ATPPROSITE-ProRule annotation
Active sitei176 – 1761Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi52 – 609ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Endocytosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 6

Organism-specific databases

MGIiMGI:1098687. 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

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 959959AP2-associated protein kinase 1PRO_0000250579Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity
Modified residuei14 – 141PhosphoserineBy similarity
Modified residuei234 – 2341PhosphotyrosineBy similarity
Modified residuei235 – 2351PhosphoserineBy similarity
Modified residuei354 – 3541PhosphothreonineBy similarity
Modified residuei389 – 3891PhosphothreonineCombined sources
Modified residuei441 – 4411PhosphothreonineBy similarity
Modified residuei604 – 6041PhosphothreonineCombined sources
Modified residuei616 – 6161PhosphoserineBy similarity
Modified residuei618 – 6181PhosphothreonineCombined sources
Modified residuei621 – 6211PhosphoserineBy similarity
Modified residuei622 – 6221PhosphoserineCombined sources
Modified residuei635 – 6351PhosphoserineCombined sources
Modified residuei648 – 6481PhosphoserineBy similarity
Modified residuei651 – 6511PhosphothreonineBy similarity
Modified residuei729 – 7291PhosphoserineBy similarity
Modified residuei844 – 8441PhosphoserineCombined sources
Modified residuei935 – 9351PhosphoserineCombined sources
Modified residuei936 – 9361PhosphoserineCombined sources

Post-translational modificationi

Autophosphorylated.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ3UHJ0.
MaxQBiQ3UHJ0.
PaxDbiQ3UHJ0.
PRIDEiQ3UHJ0.

PTM databases

iPTMnetiQ3UHJ0.
PhosphoSiteiQ3UHJ0.

Expressioni

Gene expression databases

BgeeiQ3UHJ0.
ExpressionAtlasiQ3UHJ0. baseline and differential.
GenevisibleiQ3UHJ0. MM.

Interactioni

Subunit structurei

Interacts with alpha-adaptin, AP-2, clathrin, NUMB and EPS15 isoform 2 (By similarity). 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.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi234710. 1 interaction.
IntActiQ3UHJ0. 2 interactions.
STRINGi10090.ENSMUSP00000086948.

Structurei

3D structure databases

ProteinModelPortaliQ3UHJ0.
SMRiQ3UHJ0. Positions 29-392.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini46 – 315270Protein kinasePROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi22 – 254Poly-Gly
Compositional biasi397 – 612216Gln-richAdd
BLAST
Compositional biasi656 – 6616Poly-Ala

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.
InParanoidiQ3UHJ0.
KOiK08853.
OMAiQAPIRQQ.
OrthoDBiEOG7PP566.
PhylomeDBiQ3UHJ0.
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: Q3UHJ0-1) [UniParc]FASTAAdd to basket

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 QGSSGLGSGS SGGGGSSSGL GSGYIGRVFG IGRQQVTVDE
60 70 80 90 100
VLAEGGFALV FLVRTSNGVK 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
KFQNPQAEGV NAVEDEIKKY TTLSYRAPEM VNLYSGKIIT TKADIWALGC
260 270 280 290 300
LLYKLCYFTL PFGESQVAIC DGSFTIPDNS RYSQDMHCLI RYMLEPDPDK
310 320 330 340 350
RPDIYQVSYF SFKLLKKECP VPNVQNSPIP AKLPEPVKAS EAAVKKTQPK
360 370 380 390 400
ARLTDPIPTT ETSIAPRQRP KAGQTQPNPG ILPIQPALTP RKRATVQPLP
410 420 430 440 450
QAAGPSNQPG LLPSVSQPKA QATPSQPLQS SQPKQPQAPP TPQQTPATQT
460 470 480 490 500
QGLPTQAQAT PQHQQQHLLK QQQQQQQQPQ QPTAPPQPAG TFYQQQQQQQ
510 520 530 540 550
QQQAQTQQFQ AVHPAAQQPV TAQFPVGSQG GAQQQLMQNF YHQQQQQQQQ
560 570 580 590 600
QQQLMAQQAA LQQKTAVVVP QSQAQPATAP QAAAAQEPGQ IQAPVRQQPK
610 620 630 640 650
VQTTPPPTIQ GQKVGSLTPP SSPKTQRAGH RRILSDVTHS AVFGVPASKS
660 670 680 690 700
TQLLQAAAAE ASLNKSKSAT TTPSGSPRTS QQNVSNASEG STWNPFDDDN
710 720 730 740 750
FSKLTAEELL NKDFAKLGEG KLPEKLGGSA ESLIPGFQPT QGDAFTTPSF
760 770 780 790 800
SAGTAEKRKG GQAVDSGIPL LSVSDPFIPL QVPDAPEKLI EGLKSPDTSL
810 820 830 840 850
LLPDLLPMTD PFGSTSDAVI DKADVAVESL IPGLEPPVAQ RLPSQTESVT
860 870 880 890 900
SNRTDSLTGE DSLLDCSLLS NPTAGLLEEF APIALSAPTH KAAEDSNLIS
910 920 930 940 950
GFGVAEGSEK VAEDEFDPIP VLITKNTQGG HSRNSSGSSE SSLPNLARSL

LLVDQLIDL
Length:959
Mass (Da):103,346
Last modified:October 3, 2006 - v2
Checksum:iB7D666EFD56D097A
GO
Isoform 2 (identifier: Q3UHJ0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     509-589: Missing.

Note: No experimental confirmation available.
Show »
Length:878
Mass (Da):94,661
Checksum:i3AE736423984C27D
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti79 – 791N → K in BAE27867 (PubMed:16141072).Curated
Sequence conflicti686 – 6861N → S in BAC98082 (PubMed:14621295).Curated
Sequence conflicti733 – 7331L → V in AAI41177 (PubMed:15489334).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei509 – 58981Missing in isoform 2. 1 PublicationVSP_020670Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK147363 mRNA. Translation: BAE27867.1.
AK158879 mRNA. Translation: BAE34710.1.
BC043125 mRNA. Translation: AAH43125.1.
BC141176 mRNA. Translation: AAI41177.1.
AK129272 mRNA. Translation: BAC98082.1.
CCDSiCCDS20317.1. [Q3UHJ0-2]
CCDS39544.1. [Q3UHJ0-1]
RefSeqiNP_001035195.1. NM_001040106.2. [Q3UHJ0-1]
NP_808430.2. NM_177762.6. [Q3UHJ0-2]
UniGeneiMm.221038.

Genome annotation databases

EnsembliENSMUST00000003710; ENSMUSP00000003710; ENSMUSG00000057230. [Q3UHJ0-2]
ENSMUST00000089519; ENSMUSP00000086948; ENSMUSG00000057230. [Q3UHJ0-1]
GeneIDi269774.
KEGGimmu:269774.
UCSCiuc009css.1. mouse. [Q3UHJ0-1]
uc009cst.1. mouse. [Q3UHJ0-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK147363 mRNA. Translation: BAE27867.1.
AK158879 mRNA. Translation: BAE34710.1.
BC043125 mRNA. Translation: AAH43125.1.
BC141176 mRNA. Translation: AAI41177.1.
AK129272 mRNA. Translation: BAC98082.1.
CCDSiCCDS20317.1. [Q3UHJ0-2]
CCDS39544.1. [Q3UHJ0-1]
RefSeqiNP_001035195.1. NM_001040106.2. [Q3UHJ0-1]
NP_808430.2. NM_177762.6. [Q3UHJ0-2]
UniGeneiMm.221038.

3D structure databases

ProteinModelPortaliQ3UHJ0.
SMRiQ3UHJ0. Positions 29-392.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi234710. 1 interaction.
IntActiQ3UHJ0. 2 interactions.
STRINGi10090.ENSMUSP00000086948.

PTM databases

iPTMnetiQ3UHJ0.
PhosphoSiteiQ3UHJ0.

Proteomic databases

EPDiQ3UHJ0.
MaxQBiQ3UHJ0.
PaxDbiQ3UHJ0.
PRIDEiQ3UHJ0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000003710; ENSMUSP00000003710; ENSMUSG00000057230. [Q3UHJ0-2]
ENSMUST00000089519; ENSMUSP00000086948; ENSMUSG00000057230. [Q3UHJ0-1]
GeneIDi269774.
KEGGimmu:269774.
UCSCiuc009css.1. mouse. [Q3UHJ0-1]
uc009cst.1. mouse. [Q3UHJ0-2]

Organism-specific databases

CTDi22848.
MGIiMGI:1098687. Aak1.
RougeiSearch...

Phylogenomic databases

eggNOGiKOG1989. Eukaryota.
ENOG410Y515. LUCA.
GeneTreeiENSGT00810000125451.
HOGENOMiHOG000232173.
HOVERGENiHBG080803.
InParanoidiQ3UHJ0.
KOiK08853.
OMAiQAPIRQQ.
OrthoDBiEOG7PP566.
PhylomeDBiQ3UHJ0.
TreeFamiTF317300.

Miscellaneous databases

ChiTaRSiAak1. mouse.
NextBioi393024.
PROiQ3UHJ0.
SOURCEiSearch...

Gene expression databases

BgeeiQ3UHJ0.
ExpressionAtlasiQ3UHJ0. baseline and differential.
GenevisibleiQ3UHJ0. MM.

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...

Publicationsi

« Hide 'large scale' publications
  1. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Strain: C57BL/6J.
    Tissue: Visual cortex.
  2. "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] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 473-959 (ISOFORM 2).
    Strain: C57BL/6J.
    Tissue: Brain.
  3. "Prediction of the coding sequences of mouse homologues of KIAA gene: III. The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries."
    Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., Saga Y., Nagase T., Ohara O., Koga H.
    DNA Res. 10:167-180(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 417-959 (ISOFORM 1).
    Tissue: Brain.
  4. "Comprehensive identification of phosphorylation sites in postsynaptic density preparations."
    Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.
    Mol. Cell. Proteomics 5:914-922(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brain.
  5. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  6. "The phagosomal proteome in interferon-gamma-activated macrophages."
    Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
    Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-635, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  7. "Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
    Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
    Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-604; THR-618 AND SER-622, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.
  8. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-389; THR-604; THR-618; SER-635; SER-844; SER-935 AND SER-936, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas, Spleen and Testis.
  9. "The adaptor-associated kinase 1, AAK1, is a positive regulator of the Notch pathway."
    Gupta-Rossi N., Ortica S., Meas-Yedid V., Heuss S., Moretti J., Olivo-Marin J.C., Israel A.
    J. Biol. Chem. 286:18720-18730(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NOTCH1.

Entry informationi

Entry nameiAAK1_MOUSE
AccessioniPrimary (citable) accession number: Q3UHJ0
Secondary accession number(s): B2RUJ0
, Q3TY53, Q6ZPZ6, Q80XP6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 3, 2006
Last sequence update: October 3, 2006
Last modified: May 11, 2016
This is version 102 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. 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.