UniProt functional annotation for P42858



	UniProt functional annotation for P42858

UniProt code: P42858.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: [Huntingtin]: May play a role in microtubule-mediated transport or vesicle function.

Function: [Huntingtin, myristoylated N-terminal fragment]: Promotes the formation of autophagic vesicles. {ECO:0000269|PubMed:24459296}.

Subunit: Interacts with PFN1 (PubMed:18573880). Interacts through its N-terminus with PRPF40A (PubMed:9700202). Interacts with PQBP1 (PubMed:10332029). Interacts with SETD2 (PubMed:9700202, PubMed:10958656, PubMed:11461154). Interacts with SH3GLB1 (By similarity). Interacts with SYVN (PubMed:17141218). Interacts with TPR; the interaction is inhibited by forms of Huntingtin with expanded polyglutamine stretch (PubMed:15654337). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635, PubMed:28882895, PubMed:28757145). Interacts with F8A1/F8A2/F8A3 (PubMed:29466333, PubMed:16476778). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A (PubMed:16476778). {ECO:0000250|UniProtKB:P42859, ECO:0000269|PubMed:10332029, ECO:0000269|PubMed:10958656, ECO:0000269|PubMed:11461154, ECO:0000269|PubMed:15654337, ECO:0000269|PubMed:16476778, ECO:0000269|PubMed:17141218, ECO:0000269|PubMed:18573880, ECO:0000269|PubMed:26198635, ECO:0000269|PubMed:28757145, ECO:0000269|PubMed:28882895, ECO:0000269|PubMed:29466333, ECO:0000269|PubMed:9700202}.

Subcellular location: [Huntingtin]: Cytoplasm {ECO:0000269|PubMed:15654337, ECO:0000269|PubMed:16476778, ECO:0000269|PubMed:7647777}. Nucleus {ECO:0000269|PubMed:15654337, ECO:0000269|PubMed:16391387}. Early endosome {ECO:0000269|PubMed:16476778}. Note=The mutant Huntingtin protein colocalizes with AKAP8L in the nuclear matrix of Huntington disease neurons. Shuttles between cytoplasm and nucleus in a Ran GTPase- independent manner (PubMed:15654337). Recruits onto early endosomes in a Rab5- and HAP40-dependent fashion (PubMed:16476778). {ECO:0000269|PubMed:15654337, ECO:0000269|PubMed:16476778}.

Subcellular location: [Huntingtin, myristoylated N-terminal fragment]: Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:24459296}.

Tissue specificity: Expressed in the brain cortex (at protein level). Widely expressed with the highest level of expression in the brain (nerve fibers, varicosities, and nerve endings). In the brain, the regions where it can be mainly found are the cerebellar cortex, the neocortex, the striatum, and the hippocampal formation. {ECO:0000269|PubMed:16391387}.

Domain: The N-terminal Gln-rich and Pro-rich domain has great conformational flexibility and is likely to exist in a fluctuating equilibrium of alpha-helical, random coil, and extended conformations. {ECO:0000269|PubMed:19748341}.

Ptm: [Huntingtin]: Cleaved by caspases downstream of the polyglutamine stretch (PubMed:8696339, PubMed:9535906, PubMed:10770929, PubMed:29802276). The resulting N-terminal fragments are cytotoxic and provokes apoptosis (PubMed:10770929). {ECO:0000269|PubMed:10770929, ECO:0000269|PubMed:29802276, ECO:0000269|PubMed:8696339, ECO:0000269|PubMed:9535906}.

Ptm: [Huntingtin]: Forms with expanded polyglutamine expansion are specifically ubiquitinated by SYVN1, which promotes their proteasomal degradation. {ECO:0000269|PubMed:17141218}.

Ptm: [Huntingtin]: Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response to DNA damage in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. {ECO:0000269|PubMed:17611284}.

Ptm: [Huntingtin, myristoylated N-terminal fragment]: Myristoylated at Gly-551, following proteolytic cleavage at Asp-550. {ECO:0000269|PubMed:24459296, ECO:0000269|PubMed:29802276}.

Polymorphism: The poly-Gln region of HTT is highly polymorphic (10 to 35 repeats) in the normal population and is expanded to about 36-120 repeats in Huntington disease patients. The repeat length usually increases in successive generations, but contracts also on occasion. The adjacent poly-Pro region is also polymorphic and varies between 7- 12 residues. Polyglutamine expansion leads to elevated susceptibility to apopain cleavage and likely result in accelerated neuronal apoptosis (PubMed:8696339). {ECO:0000269|PubMed:8696339}.

Disease: Huntington disease (HD) [MIM:143100]: A neurodegenerative disorder characterized by involuntary movements (chorea), general motor impairment, psychiatric disorders and dementia. Onset of the disease occurs usually in the third or fourth decade of life. Onset and clinical course depend on the degree of poly-Gln repeat expansion, longer expansions resulting in earlier onset and more severe clinical manifestations. Neuropathology of Huntington disease displays a distinctive pattern with loss of neurons, especially in the caudate and putamen. {ECO:0000269|PubMed:8458085}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Lopes-Maciel-Rodan syndrome (LOMARS) [MIM:617435]: An autosomal recessive neurodevelopmental disorder characterized by developmental regression in infancy, delayed psychomotor development, severe intellectual disability, and cerebral and cerebellar atrophy. Additional features include swallowing problems, dystonia, bradykinesia, and continuous manual stereotypies without chorea. Some patients manifest seizures. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:27329733}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the huntingtin family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		[Huntingtin]: May play a role in microtubule-mediated transport or vesicle function.



Function:		[Huntingtin, myristoylated N-terminal fragment]: Promotes the formation of autophagic vesicles. {ECO:0000269\|PubMed:24459296}.


Subunit:		Interacts with PFN1 (PubMed:18573880). Interacts through its N-terminus with PRPF40A (PubMed:9700202). Interacts with PQBP1 (PubMed:10332029). Interacts with SETD2 (PubMed:9700202, PubMed:10958656, PubMed:11461154). Interacts with SH3GLB1 (By similarity). Interacts with SYVN (PubMed:17141218). Interacts with TPR; the interaction is inhibited by forms of Huntingtin with expanded polyglutamine stretch (PubMed:15654337). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635, PubMed:28882895, PubMed:28757145). Interacts with F8A1/F8A2/F8A3 (PubMed:29466333, PubMed:16476778). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A (PubMed:16476778). {ECO:0000250\|UniProtKB:P42859, ECO:0000269\|PubMed:10332029, ECO:0000269\|PubMed:10958656, ECO:0000269\|PubMed:11461154, ECO:0000269\|PubMed:15654337, ECO:0000269\|PubMed:16476778, ECO:0000269\|PubMed:17141218, ECO:0000269\|PubMed:18573880, ECO:0000269\|PubMed:26198635, ECO:0000269\|PubMed:28757145, ECO:0000269\|PubMed:28882895, ECO:0000269\|PubMed:29466333, ECO:0000269\|PubMed:9700202}.
Subcellular location:		[Huntingtin]: Cytoplasm {ECO:0000269\|PubMed:15654337, ECO:0000269\|PubMed:16476778, ECO:0000269\|PubMed:7647777}. Nucleus {ECO:0000269\|PubMed:15654337, ECO:0000269\|PubMed:16391387}. Early endosome {ECO:0000269\|PubMed:16476778}. Note=The mutant Huntingtin protein colocalizes with AKAP8L in the nuclear matrix of Huntington disease neurons. Shuttles between cytoplasm and nucleus in a Ran GTPase- independent manner (PubMed:15654337). Recruits onto early endosomes in a Rab5- and HAP40-dependent fashion (PubMed:16476778). {ECO:0000269\|PubMed:15654337, ECO:0000269\|PubMed:16476778}.
Subcellular location:		[Huntingtin, myristoylated N-terminal fragment]: Cytoplasmic vesicle, autophagosome {ECO:0000269\|PubMed:24459296}.
Tissue specificity:		Expressed in the brain cortex (at protein level). Widely expressed with the highest level of expression in the brain (nerve fibers, varicosities, and nerve endings). In the brain, the regions where it can be mainly found are the cerebellar cortex, the neocortex, the striatum, and the hippocampal formation. {ECO:0000269\|PubMed:16391387}.
Domain:		The N-terminal Gln-rich and Pro-rich domain has great conformational flexibility and is likely to exist in a fluctuating equilibrium of alpha-helical, random coil, and extended conformations. {ECO:0000269\|PubMed:19748341}.
Ptm:		[Huntingtin]: Cleaved by caspases downstream of the polyglutamine stretch (PubMed:8696339, PubMed:9535906, PubMed:10770929, PubMed:29802276). The resulting N-terminal fragments are cytotoxic and provokes apoptosis (PubMed:10770929). {ECO:0000269\|PubMed:10770929, ECO:0000269\|PubMed:29802276, ECO:0000269\|PubMed:8696339, ECO:0000269\|PubMed:9535906}.
Ptm:		[Huntingtin]: Forms with expanded polyglutamine expansion are specifically ubiquitinated by SYVN1, which promotes their proteasomal degradation. {ECO:0000269\|PubMed:17141218}.
Ptm:		[Huntingtin]: Phosphorylation at Ser-1179 and Ser-1199 by CDK5 in response to DNA damage in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. {ECO:0000269\|PubMed:17611284}.
Ptm:		[Huntingtin, myristoylated N-terminal fragment]: Myristoylated at Gly-551, following proteolytic cleavage at Asp-550. {ECO:0000269\|PubMed:24459296, ECO:0000269\|PubMed:29802276}.
Polymorphism:		The poly-Gln region of HTT is highly polymorphic (10 to 35 repeats) in the normal population and is expanded to about 36-120 repeats in Huntington disease patients. The repeat length usually increases in successive generations, but contracts also on occasion. The adjacent poly-Pro region is also polymorphic and varies between 7- 12 residues. Polyglutamine expansion leads to elevated susceptibility to apopain cleavage and likely result in accelerated neuronal apoptosis (PubMed:8696339). {ECO:0000269\|PubMed:8696339}.
Disease:		Huntington disease (HD) [MIM:143100]: A neurodegenerative disorder characterized by involuntary movements (chorea), general motor impairment, psychiatric disorders and dementia. Onset of the disease occurs usually in the third or fourth decade of life. Onset and clinical course depend on the degree of poly-Gln repeat expansion, longer expansions resulting in earlier onset and more severe clinical manifestations. Neuropathology of Huntington disease displays a distinctive pattern with loss of neurons, especially in the caudate and putamen. {ECO:0000269\|PubMed:8458085}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Lopes-Maciel-Rodan syndrome (LOMARS) [MIM:617435]: An autosomal recessive neurodevelopmental disorder characterized by developmental regression in infancy, delayed psychomotor development, severe intellectual disability, and cerebral and cerebellar atrophy. Additional features include swallowing problems, dystonia, bradykinesia, and continuous manual stereotypies without chorea. Some patients manifest seizures. {ECO:0000269\|PubMed:26740508, ECO:0000269\|PubMed:27329733}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the huntingtin family. {ECO:0000305}.