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Protein

Huntingtin-associated protein 1

Gene

Hap1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Originally identified as neuronal protein that specifically associates with HTT/huntingtin and the binding is enhanced by an expanded polyglutamine repeat within HTT possibly affecting HAP1 interaction properties. Both HTT and HAP1 are involved in intracellular trafficking and HAP1 is proposed to link HTT to motor proteins and/or transport cargos. Seems to play a role in vesicular transport within neurons and axons such as from early endosomes to late endocytic compartments and to promote neurite outgrowth. The vesicular transport function via association with microtubule-dependent transporters can be attenuated by association with mutant HTT. Involved in the axonal transport of BDNF and its activity-dependent secretion; the function seems to involve HTT, DCTN1 and a complex with SORT1. Involved in APP trafficking and seems to faciltate APP anterograde transport and membrane insertion thereby possibly reducing processing into amyloid beta. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptors to synapses; the function is dependent on kinesin motor protein KIF5 and is disrupted by HTT with expanded polyglutamine repeat. Involved in regulation of autophagosome motility by promoting efficient retrograde axonal transport. Seems to be involved in regulation of membrane receptor recycling and degradation, and respective signal transduction, including GABA(A) receptors, tyrosine kinase receptors, EGFR, IP3 receptor and androgen receptor. Among others suggested to be involved in control of feeding behavior (involving hypothalamic GABA(A) receptors), cerebellar and brainstem development (involving AHI1 and NTRK1/TrkA), postnatal neurogenesis (involving hypothalamic NTRK2/TrkB regulating the number of Npyr1-expressing cells), and ITPR1/InsP3R1-mediated Ca2+ release (involving HTT and possibly the effect of mutant HTT). Via association with DCTN1/dynactin p150-glued and HTT/huntingtin involved in cytoplasmic retention of REST in neurons. May be involved in ciliogenesiss; however, reports are conflicting: PubMed:21985783 reports that Hap1 is required for ciliogenesis in primary cortical neurons and proposes that HTT interacts with PCM1 through HAP1; PubMed:23532844 reports that mice with disrupted Hap1 display normal cilium formation and function. Involved in regulation of exocytosis. Isoform A but not isoform B seems to be involved in formation of cytoplasmic inclusion bodies (STBs). In case of anomalous expression of TBP, can sequester a subset of TBP into STBs; sequestration is enhanced by an expanded polyglutamine repeat within TBP.8 Publications

GO - Molecular functioni

GO - Biological processi

  • anterograde axonal transport Source: UniProtKB
  • autophagy Source: UniProtKB-KW
  • cell projection organization Source: UniProtKB-KW
  • cerebellum development Source: UniProtKB
  • exocytosis Source: UniProtKB-KW
  • hypothalamus cell differentiation Source: UniProtKB
  • negative regulation of beta-amyloid formation Source: UniProtKB
  • negative regulation of cytoplasmic translation Source: CACAO
  • neurogenesis Source: CACAO
  • neurotrophin TRK receptor signaling pathway Source: UniProtKB
  • positive regulation of epidermal growth factor receptor signaling pathway Source: UniProtKB
  • positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity Source: UniProtKB
  • positive regulation of neurogenesis Source: UniProtKB
  • positive regulation of neurotrophin production Source: UniProtKB
  • positive regulation of nonmotile primary cilium assembly Source: UniProtKB
  • positive regulation of synaptic transmission, GABAergic Source: UniProtKB
  • protein localization Source: MGI
  • protein transport Source: UniProtKB-KW
  • regulation of exocytosis Source: UniProtKB
  • regulation of organelle transport along microtubule Source: UniProtKB
  • retrograde axonal transport Source: UniProtKB
  • vesicle transport along microtubule Source: MGI
Complete GO annotation...

Keywords - Biological processi

Autophagy, Cilium biogenesis/degradation, Exocytosis, Protein transport, Transport

Names & Taxonomyi

Protein namesi
Recommended name:
Huntingtin-associated protein 1
Short name:
HAP-1
Gene namesi
Name:Hap1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:1261831. Hap1.

Subcellular locationi

GO - Cellular componenti

  • autophagosome Source: UniProtKB
  • axon cytoplasm Source: GOC
  • cell junction Source: UniProtKB-KW
  • centriole Source: MGI
  • centrosome Source: CACAO
  • cytoplasmic, membrane-bounded vesicle Source: MGI
  • endoplasmic reticulum Source: UniProtKB-SubCell
  • inclusion body Source: MGI
  • lysosome Source: UniProtKB-SubCell
  • mitochondrion Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB-SubCell
  • synaptic vesicle Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell projection, Cytoplasm, Cytoplasmic vesicle, Cytoskeleton, Endoplasmic reticulum, Lysosome, Mitochondrion, Nucleus, Synapse

Pathology & Biotechi

Disruption phenotypei

Depressed postnatal feeding behavior leading to premature death latest at P9. Degeneration in hypothalamic regions that control feeding behavior.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 628628Huntingtin-associated protein 1PRO_0000083895Add
BLAST

Post-translational modificationi

Isoform A is phosphorylated on 'Thr-598'.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiO35668.
PaxDbiO35668.
PRIDEiO35668.

PTM databases

iPTMnetiO35668.
PhosphoSiteiO35668.

Expressioni

Gene expression databases

BgeeiO35668.
CleanExiMM_HAP1.
ExpressionAtlasiO35668. baseline and differential.
GenevisibleiO35668. MM.

Interactioni

Subunit structurei

Self-associates. Interacts with HTT/huntingtin; enhanced by an expanded polyglutamine repeat within HTT. Isoform A interacts with DCTN1; decreased in presence of HTT with expanded polyglutamine repeat; decreased by phosphorylation of Hap1 isoform A at Thr-598. Isoform A interacts with KLC2; decreased by phosphorylation of Hap1 isoform A at Thr-598. Isoform A interacts with ITPR1 and APP. Isoform A interacts with AR; decreased by an expanded polyglutamine repeat within AR. Isoform A interacts with YWHAZ; enhanced by phosphorylation of Hap1 isoform A at Thr-598. Isoform A interacts with BDNF and SORT1; probably forming a complex involved in proBDNF trafficking, degradation and processing. Interacts with TBP, AHI1, HGS and KALRN. Interacts with KIF5A, KIF5B, KIF5C and GABRB3; indicative for an HAP1:KIF5 complex transporting a GABA(A) receptor as cargo. Interacts with ATXN3; in STBs. Interacts with NTRK2; HAP1 stabilizes association of NTRK2 with SORT1 preventing NTRK2 degradation. Interacts with CCDC113.By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Ahi1Q8K3E53EBI-473704,EBI-4280729
Klc2B2GV743EBI-473719,EBI-978371From a different organism.

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200207. 3 interactions.
DIPiDIP-32510N.
IntActiO35668. 14 interactions.
MINTiMINT-3978384.
STRINGi10090.ENSMUSP00000133356.

Structurei

3D structure databases

ProteinModelPortaliO35668.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini79 – 403325HAP1 N-terminalAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni152 – 319168Sufficient for interaction with KIF5BBy similarityAdd
BLAST
Regioni157 – 261105Interaction with TBPAdd
BLAST
Regioni276 – 444169Sufficient for self-association and interaction with HDBy similarityAdd
BLAST
Regioni473 – 582110Interaction with TBPAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili168 – 301134Sequence analysisAdd
BLAST
Coiled coili327 – 36741Sequence analysisAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi214 – 2207Poly-Asp
Compositional biasi221 – 528308Glu-richAdd
BLAST
Compositional biasi224 – 23613Poly-GluAdd
BLAST
Compositional biasi467 – 4704Poly-Pro

Sequence similaritiesi

Contains 1 HAP1 N-terminal domain.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG4360. Eukaryota.
ENOG410XSWD. LUCA.
GeneTreeiENSGT00390000003132.
HOGENOMiHOG000230957.
HOVERGENiHBG031599.
InParanoidiO35668.
KOiK04647.
OMAiIWKTPAA.
OrthoDBiEOG7CRTSM.
PhylomeDBiO35668.
TreeFamiTF323495.

Family and domain databases

InterProiIPR006933. HAP1_N.
[Graphical view]
PfamiPF04849. HAP1_N. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform B (identifier: O35668-1) [UniParc]FASTAAdd to basket

Also known as: Long

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
MRPKEQVQSG AGDGTGSGDP AAGTPTTQPA VGPAPEPSAE PKPAPAQGTG
60 70 80 90 100
SGQKSGSRTK TGSFCRSMII GDSDAPWTRY VFQGPYGPRA TGLGTGKAEG
110 120 130 140 150
IWKTPAAYIG RRPGVSGPER AAFIRELQEA LCPNPPPTKK ITEDDVKVML
160 170 180 190 200
YLLEEKERDL NTAARIGQSL VKQNSVLMEE NNKLETMLGS AREEILHLRK
210 220 230 240 250
QVNLRDDLLQ LYSDSDDDDD EEDEEDEEEG EEEEREGQRD QDQQHDHPYG
260 270 280 290 300
APKPHPKAET AHRCPQLETL QQKLRLLEEE NDHLREEASH LDNLEDEEQM
310 320 330 340 350
LILECVEQFS EASQQMAELS EVLVLRLEGY ERQQKEITQL QAEITKLQQR
360 370 380 390 400
CQSYGAQTEK LQQMLASEKG IHSESLRAGS YMQDYGSRPR DRQEDGKSHR
410 420 430 440 450
QRSSMPAGSV THYGYSVPLD ALPSFPETLA EELRTSLRKF ITDPAYFMER
460 470 480 490 500
RDTHCREGRK KEQRAMPPPP AQDLKPPEDF EAPEELVPEE ELGAIEEVGT
510 520 530 540 550
AEDGQAEENE QASEETEAWE EVEPEVDETT RMNVVVSALE ASGLGPSHLD
560 570 580 590 600
MKYVLQQLSN WQDAHSKRQQ KQKVVPKDSP TPQQQTNMGG GILEQQPRVP
610 620
TQDSQRLEED RATHSPSARE EEGPSGAT
Length:628
Mass (Da):70,116
Last modified:January 1, 1998 - v1
Checksum:iAF516F61D6AB7CCB
GO
Isoform A (identifier: O35668-2) [UniParc]FASTAAdd to basket

Also known as: Short

The sequence of this isoform differs from the canonical sequence as follows:
     578-628: DSPTPQQQTNMGGGILEQQPRVPTQDSQRLEEDRATHSPSAREEEGPSGAT → GECSRRGHPPASGTSFRSSTI

Show »
Length:598
Mass (Da):66,804
Checksum:i744EA32CB65A92F5
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei578 – 62851DSPTP…PSGAT → GECSRRGHPPASGTSFRSST I in isoform A. 1 PublicationVSP_004279Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ000262 mRNA. Translation: CAA03978.1.
AJ002271 mRNA. Translation: CAA05286.1.
AJ003128 Genomic DNA. Translation: CAA05883.1.
BC034089 mRNA. Translation: AAH34089.1.
BC053043 mRNA. Translation: AAH53043.1.
CCDSiCCDS25419.1. [O35668-2]
CCDS56806.1. [O35668-1]
RefSeqiNP_034534.1. NM_010404.3. [O35668-2]
NP_817090.1. NM_177981.2. [O35668-1]
UniGeneiMm.281700.

Genome annotation databases

EnsembliENSMUST00000103124; ENSMUSP00000099413; ENSMUSG00000006930. [O35668-2]
ENSMUST00000138603; ENSMUSP00000133356; ENSMUSG00000006930. [O35668-1]
GeneIDi15114.
KEGGimmu:15114.
UCSCiuc007lkx.2. mouse. [O35668-2]
uc007lky.2. mouse. [O35668-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ000262 mRNA. Translation: CAA03978.1.
AJ002271 mRNA. Translation: CAA05286.1.
AJ003128 Genomic DNA. Translation: CAA05883.1.
BC034089 mRNA. Translation: AAH34089.1.
BC053043 mRNA. Translation: AAH53043.1.
CCDSiCCDS25419.1. [O35668-2]
CCDS56806.1. [O35668-1]
RefSeqiNP_034534.1. NM_010404.3. [O35668-2]
NP_817090.1. NM_177981.2. [O35668-1]
UniGeneiMm.281700.

3D structure databases

ProteinModelPortaliO35668.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200207. 3 interactions.
DIPiDIP-32510N.
IntActiO35668. 14 interactions.
MINTiMINT-3978384.
STRINGi10090.ENSMUSP00000133356.

PTM databases

iPTMnetiO35668.
PhosphoSiteiO35668.

Proteomic databases

MaxQBiO35668.
PaxDbiO35668.
PRIDEiO35668.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000103124; ENSMUSP00000099413; ENSMUSG00000006930. [O35668-2]
ENSMUST00000138603; ENSMUSP00000133356; ENSMUSG00000006930. [O35668-1]
GeneIDi15114.
KEGGimmu:15114.
UCSCiuc007lkx.2. mouse. [O35668-2]
uc007lky.2. mouse. [O35668-1]

Organism-specific databases

CTDi9001.
MGIiMGI:1261831. Hap1.

Phylogenomic databases

eggNOGiKOG4360. Eukaryota.
ENOG410XSWD. LUCA.
GeneTreeiENSGT00390000003132.
HOGENOMiHOG000230957.
HOVERGENiHBG031599.
InParanoidiO35668.
KOiK04647.
OMAiIWKTPAA.
OrthoDBiEOG7CRTSM.
PhylomeDBiO35668.
TreeFamiTF323495.

Miscellaneous databases

ChiTaRSiHap1. mouse.
PROiO35668.
SOURCEiSearch...

Gene expression databases

BgeeiO35668.
CleanExiMM_HAP1.
ExpressionAtlasiO35668. baseline and differential.
GenevisibleiO35668. MM.

Family and domain databases

InterProiIPR006933. HAP1_N.
[Graphical view]
PfamiPF04849. HAP1_N. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "HAP1-huntingtin interactions do not contribute to the molecular pathology in Huntingtons disease transgenic mice."
    Bertaux F., Sharp A.H., Ross C.A., Lehrach H., Bates G.P., Wanker E.
    FEBS Lett. 426:229-232(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
    Strain: BALB/cJ.
    Tissue: Brain.
  2. "Gene structure and map location of the murine homolog of the Huntington-associated protein, Hap1."
    Nasir J., Duan K., Nichol K., Engelender S., Ashworth R., Colomer V., Thomas S., Disteche C.M., Hayden M.R., Ross C.A.
    Mamm. Genome 9:565-570(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM A).
    Strain: 129/SvJ.
  3. "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 B).
    Strain: C57BL/6J.
    Tissue: Brain and Eye.
  4. "Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington's disease."
    Li S.H., Yu Z.X., Li C.L., Nguyen H.P., Zhou Y.X., Deng C., Li X.J.
    J. Neurosci. 23:6956-6964(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  5. "HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca release in primary culture of striatal medium spiny neurons."
    Tang T.S., Tu H., Orban P.C., Chan E.Y., Hayden M.R., Bezprozvanny I.
    Eur. J. Neurosci. 20:1779-1787(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. "HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBP(CORE)."
    Prigge J.R., Schmidt E.E.
    BMC Mol. Biol. 8:76-76(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH TBP.
  7. "Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice."
    Sheng G., Xu X., Lin Y.F., Wang C.E., Rong J., Cheng D., Peng J., Jiang X., Li S.H., Li X.J.
    J. Clin. Invest. 118:2785-2795(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH AHI1.
  8. "Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease."
    Keryer G., Pineda J.R., Liot G., Kim J., Dietrich P., Benstaali C., Smith K., Cordelieres F.P., Spassky N., Ferrante R.J., Dragatsis I., Saudou F.
    J. Clin. Invest. 121:4372-4382(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions."
    Tuz K., Hsiao Y.C., Juarez O., Shi B., Harmon E.Y., Phelps I.G., Lennartz M.R., Glass I.A., Doherty D., Ferland R.J.
    J. Biol. Chem. 288:13676-13694(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH AHI1.
  10. "Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting."
    Xiang J., Yang H., Zhao T., Sun M., Xu X., Zhou X.F., Li S.H., Li X.J.
    J. Clin. Invest. 124:85-98(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  11. "The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation."
    Wong Y.C., Holzbaur E.L.
    J. Neurosci. 34:1293-1305(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  12. "Huntingtin-associated protein 1 regulates exocytosis, vesicle docking, readily releasable pool size and fusion pore stability in mouse chromaffin cells."
    Mackenzie K.D., Duffield M.D., Peiris H., Phillips L., Zanin M.P., Teo E.H., Zhou X.F., Keating D.J.
    J. Physiol. (Lond.) 592:1505-1518(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiHAP1_MOUSE
AccessioniPrimary (citable) accession number: O35668
Secondary accession number(s): O35636
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 10, 2002
Last sequence update: January 1, 1998
Last modified: July 6, 2016
This is version 113 of the entry and version 1 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. 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.