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Protein

Huntingtin-associated protein 1

Gene

HAP1

Organism
Homo sapiens (Human)
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), 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 ciliogenesis. Involved in regulation of exocytosis. 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. HAP1-containing STBs have been proposed to play a protective role against neurodegeneration in Huntigton disease (HD) and spinocerebellar ataxia 17 (SCA17).1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

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

Enzyme and pathway databases

SIGNORiP54257.

Names & Taxonomyi

Protein namesi
Recommended name:
Huntingtin-associated protein 1
Short name:
HAP-1
Alternative name(s):
Neuroan 1
Gene namesi
Name:HAP1
Synonyms:HAP2, HLP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:4812. HAP1.

Subcellular locationi

  • Cytoplasm 1 Publication
  • Cell projectionaxon 1 Publication
  • Cytoplasmcytoskeleton By similarity
  • Lysosome By similarity
  • Endoplasmic reticulum By similarity
  • Cytoplasmic vesiclesecretory vesiclesynaptic vesicle By similarity
  • Mitochondrion 1 Publication
  • Nucleus By similarity
  • Cytoplasmic vesicleautophagosome By similarity

  • Note: Localizes to large nonmembrane-bound cytoplasmic bodies found in various types of neurons, called stigmoid bodies (STBs). Localization to neuronal processes and neurite tips is decreased by YWHAZ. In the nucleus localizes to nuclear rods (By similarity).By similarity

GO - Cellular componenti

  • actin cytoskeleton Source: ProtInc
  • autophagosome Source: UniProtKB-SubCell
  • axon cytoplasm Source: GOC
  • cell junction Source: UniProtKB-KW
  • centriole Source: Ensembl
  • cytoskeleton Source: ProtInc
  • endoplasmic reticulum Source: UniProtKB-SubCell
  • inclusion body Source: UniProtKB
  • 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

Organism-specific databases

PharmGKBiPA29188.

Polymorphism and mutation databases

BioMutaiHAP1.
DMDMi290457683.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 671671Huntingtin-associated protein 1PRO_0000083894Add
BLAST

Proteomic databases

EPDiP54257.
PeptideAtlasiP54257.
PRIDEiP54257.

PTM databases

iPTMnetiP54257.
PhosphoSiteiP54257.

Expressioni

Tissue specificityi

Predominantly expressed in brain. Selectively expressed in neurons.

Gene expression databases

BgeeiENSG00000173805.
CleanExiHS_HAP1.
ExpressionAtlasiP54257. baseline and differential.
GenevisibleiP54257. HS.

Organism-specific databases

HPAiHPA023394.

Interactioni

Subunit structurei

Self-associates. Interacts with HTT/huntingtin; enhanced by an expanded polyglutamine repeat within HTT. Interacts with DCTN1; decreased in presence of HTT with expanded polyglutamine repeat. Interacts with KLC2. Interacts with ITPR1 and APP. Interacts with AR; decreased by an expanded polyglutamine repeat within AR. Interacts with YWHAZ. 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 with ATXN3 poly-Gln region with 27 repeats (normal population) and 79 repeats (spinocerebellar ataxia 3 (SCA3) patients) associating in the same strength. Interacts with NTRK2; HAP1 stabilizes association of NTRK2 with SORT1 preventing NTRK2 degradation. Interacts with CCDC113.5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AHI1Q8N1573EBI-712814,EBI-1049056
ATXN3P542526EBI-712814,EBI-946046
HTTP428588EBI-9392340,EBI-466029

GO - Molecular functioni

Protein-protein interaction databases

BioGridi114480. 67 interactions.
IntActiP54257. 50 interactions.
MINTiMINT-1410317.

Structurei

3D structure databases

ProteinModelPortaliP54257.
SMRiP54257. Positions 217-246.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini106 – 461356HAP1 N-terminalAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili212 – 427216Sequence analysisAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi261 – 601341Glu-richAdd
BLAST

Sequence similaritiesi

Contains 1 HAP1 N-terminal domain.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

GeneTreeiENSGT00390000003132.
HOVERGENiHBG031599.
InParanoidiP54257.
KOiK04647.
OMAiIWKTPAA.
OrthoDBiEOG091G0LLD.
PhylomeDBiP54257.
TreeFamiTF323495.

Family and domain databases

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

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: P54257-1) [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
MRPKRLGRCC AGSRLGPGDP AALTCAPSPS ASPAPEPSAQ PQARGTGQRV
60 70 80 90 100
GSRATSGSQF LSEARTGARP ASEAGAKAGA RRPSAFSAIQ GDVRSMPDNS
110 120 130 140 150
DAPWTRFVFQ GPFGSRATGR GTGKAAGIWK TPAAYVGRRP GVSGPERAAF
160 170 180 190 200
IRELEEALCP NLPPPVKKIT QEDVKVMLYL LEELLPPVWE SVTYGMVLQR
210 220 230 240 250
ERDLNTAARI GQSLVKQNSV LMEENSKLEA LLGSAKEEIL YLRHQVNLRD
260 270 280 290 300
ELLQLYSDSD EEDEDEEEEE EEKEAEEEQE EEEAEEDLQC AHPCDAPKLI
310 320 330 340 350
SQEALLHQHH CPQLEALQEK LRLLEEENHQ LREEASQLDT LEDEEQMLIL
360 370 380 390 400
ECVEQFSEAS QQMAELSEVL VLRLENYERQ QQEVARLQAQ VLKLQQRCRM
410 420 430 440 450
YGAETEKLQK QLASEKEIQM QLQEESVWVG SQLQDLREKY MDCGGMLIEM
460 470 480 490 500
QEEVKTLRQQ PPVSTGSATH YPYSVPLETL PGFQETLAEE LRTSLRRMIS
510 520 530 540 550
DPVYFMERNY EMPRGDTSSL RYDFRYSEDR EQVRGFEAEE GLMLAADIMR
560 570 580 590 600
GEDFTPAEEF VPQEELGAAK KVPAEEGVME EAELVSEETE GWEEVELELD
610 620 630 640 650
EATRMNVVTS ALEASGLGPS HLDMNYVLQQ LANWQDAHYR RQLRWKMLQK
660 670
GECPHGALPA ASRTSCRSSC R
Note: No experimental confirmation available.
Length:671
Mass (Da):75,506
Last modified:March 2, 2010 - v3
Checksum:i10971B807941B4EE
GO
Isoform 2 (identifier: P54257-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     426-477: Missing.

Show »
Length:619
Mass (Da):69,640
Checksum:i6BF49457C5178317
GO
Isoform 3 (identifier: P54257-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     401-477: Missing.

Show »
Length:594
Mass (Da):66,705
Checksum:iF308765B0A0DCFDA
GO
Isoform 4 (identifier: P54257-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     183-183: E → EVCTAFLIQ
     401-477: Missing.

Show »
Length:602
Mass (Da):67,582
Checksum:i3100300659F29F84
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti184 – 19916Missing in CAB82785 (Ref. 6) CuratedAdd
BLAST
Sequence conflicti573 – 5731P → L in BAB13952 (PubMed:14702039).Curated
Sequence conflicti579 – 5791M → V in AAC39861 (PubMed:9668110).Curated
Sequence conflicti611 – 6111A → T in AAC50297 (PubMed:7477378).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti4 – 41K → R.3 Publications
Corresponds to variant rs4796604 [ dbSNP | Ensembl ].
VAR_046736
Natural varianti58 – 581S → T.3 Publications
Corresponds to variant rs4796603 [ dbSNP | Ensembl ].
VAR_046737
Natural varianti357 – 3571S → L.3 Publications
Corresponds to variant rs4796693 [ dbSNP | Ensembl ].
VAR_046738
Natural varianti408 – 4081L → F.
Corresponds to variant rs35612698 [ dbSNP | Ensembl ].
VAR_056906
Natural varianti437 – 4371R → W.1 Publication
Corresponds to variant rs11867808 [ dbSNP | Ensembl ].
VAR_046739
Natural varianti483 – 4831F → L.
Corresponds to variant rs8075017 [ dbSNP | Ensembl ].
VAR_046741
Natural varianti488 – 4881A → V.
Corresponds to variant rs34853043 [ dbSNP | Ensembl ].
VAR_046742
Natural varianti493 – 4931T → M May influence the age-at-onset of Huntington disease; increases binding to mutated HTT; influences HTT degradation. 2 Publications
Corresponds to variant rs4523977 [ dbSNP | Ensembl ].
VAR_056907
Natural varianti557 – 5571A → V.
Corresponds to variant rs34853043 [ dbSNP | Ensembl ].
VAR_056908
Natural varianti560 – 5601F → L.6 Publications
Corresponds to variant rs8075017 [ dbSNP | Ensembl ].
VAR_062817
Natural varianti656 – 6561G → R.
Corresponds to variant rs34044330 [ dbSNP | Ensembl ].
VAR_056909

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei183 – 1831E → EVCTAFLIQ in isoform 4. 1 PublicationVSP_038754
Alternative sequencei401 – 47777Missing in isoform 3 and isoform 4. 2 PublicationsVSP_004277Add
BLAST
Alternative sequencei426 – 47752Missing in isoform 2. 2 PublicationsVSP_004278Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF040723 mRNA. Translation: AAC39861.1.
AJ012824 Genomic DNA. Translation: CAC09418.1.
AK022007 mRNA. Translation: BAB13952.1.
AC109319 Genomic DNA. No translation available.
AB209105 mRNA. Translation: BAD92342.1.
AJ224877 Genomic DNA. Translation: CAB82785.1.
U38371 mRNA. Translation: AAC50297.1.
CCDSiCCDS11406.1. [P54257-2]
CCDS42338.1. [P54257-4]
CCDS42339.1. [P54257-3]
PIRiS72555.
RefSeqiNP_001073339.1. NM_001079870.1. [P54257-4]
NP_001073340.1. NM_001079871.1. [P54257-3]
NP_817084.2. NM_177977.2. [P54257-2]
UniGeneiHs.158300.

Genome annotation databases

EnsembliENST00000310778; ENSP00000309392; ENSG00000173805. [P54257-1]
ENST00000341193; ENSP00000343170; ENSG00000173805. [P54257-4]
ENST00000347901; ENSP00000334002; ENSG00000173805. [P54257-2]
ENST00000393939; ENSP00000377513; ENSG00000173805. [P54257-3]
GeneIDi9001.
KEGGihsa:9001.
UCSCiuc002hxm.2. human. [P54257-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF040723 mRNA. Translation: AAC39861.1.
AJ012824 Genomic DNA. Translation: CAC09418.1.
AK022007 mRNA. Translation: BAB13952.1.
AC109319 Genomic DNA. No translation available.
AB209105 mRNA. Translation: BAD92342.1.
AJ224877 Genomic DNA. Translation: CAB82785.1.
U38371 mRNA. Translation: AAC50297.1.
CCDSiCCDS11406.1. [P54257-2]
CCDS42338.1. [P54257-4]
CCDS42339.1. [P54257-3]
PIRiS72555.
RefSeqiNP_001073339.1. NM_001079870.1. [P54257-4]
NP_001073340.1. NM_001079871.1. [P54257-3]
NP_817084.2. NM_177977.2. [P54257-2]
UniGeneiHs.158300.

3D structure databases

ProteinModelPortaliP54257.
SMRiP54257. Positions 217-246.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114480. 67 interactions.
IntActiP54257. 50 interactions.
MINTiMINT-1410317.

PTM databases

iPTMnetiP54257.
PhosphoSiteiP54257.

Polymorphism and mutation databases

BioMutaiHAP1.
DMDMi290457683.

Proteomic databases

EPDiP54257.
PeptideAtlasiP54257.
PRIDEiP54257.

Protocols and materials databases

DNASUi9001.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000310778; ENSP00000309392; ENSG00000173805. [P54257-1]
ENST00000341193; ENSP00000343170; ENSG00000173805. [P54257-4]
ENST00000347901; ENSP00000334002; ENSG00000173805. [P54257-2]
ENST00000393939; ENSP00000377513; ENSG00000173805. [P54257-3]
GeneIDi9001.
KEGGihsa:9001.
UCSCiuc002hxm.2. human. [P54257-1]

Organism-specific databases

CTDi9001.
GeneCardsiHAP1.
H-InvDBHIX0013817.
HGNCiHGNC:4812. HAP1.
HPAiHPA023394.
MIMi600947. gene.
neXtProtiNX_P54257.
PharmGKBiPA29188.
GenAtlasiSearch...

Phylogenomic databases

GeneTreeiENSGT00390000003132.
HOVERGENiHBG031599.
InParanoidiP54257.
KOiK04647.
OMAiIWKTPAA.
OrthoDBiEOG091G0LLD.
PhylomeDBiP54257.
TreeFamiTF323495.

Enzyme and pathway databases

SIGNORiP54257.

Miscellaneous databases

GenomeRNAii9001.
PROiP54257.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000173805.
CleanExiHS_HAP1.
ExpressionAtlasiP54257. baseline and differential.
GenevisibleiP54257. HS.

Family and domain databases

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

Entry informationi

Entry nameiHAP1_HUMAN
AccessioniPrimary (citable) accession number: P54257
Secondary accession number(s): A8MQB5
, O75358, Q59GK4, Q9H4G3, Q9HA98, Q9NY90
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: March 2, 2010
Last modified: September 7, 2016
This is version 132 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

Miscellaneous

Was not found in huntingtin-containing aggregates in huntigton disease (HD) tissue.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: 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. 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.