Huntingtin

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Huntingtin

Crystallographic structure of the N-terminal region of the human Huntingtin protein with an artificially attached Maltose-Binding protein used for crystallographic purposes.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsHTT; HD; IT15
External IDsOMIM: 613004 MGI: 96067 HomoloGene: 1593 ChEMBL: 5514 GeneCards: HTT Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez306415194
EnsemblENSG00000197386ENSMUSG00000029104
UniProtP42858P42859
RefSeq (mRNA)NM_002111NM_010414
RefSeq (protein)NP_002102NP_034544
Location (UCSC)Chr 4:
3.08 – 3.25 Mb		Chr 5:
34.76 – 34.91 Mb
PubMed search
This box:

The huntingtin gene, also called HTT or HD (Huntington disease) gene, is the IT15 ("interesting transcript 15") gene which codes for a protein called the huntingtin protein.[2] The gene and its product are under heavy investigation as part of Huntington's disease clinical research.

It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, it contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), it contains greater than 36 glutamine residues (highest reported repeat length is about 250).[3] Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.

The mass of huntingtin protein is dependent largely on the number of glutamine residues it has, the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in signaling, transporting materials, binding proteins and other structures, and protecting against programmed cell death (apoptosis). The huntingtin protein is required for normal development before birth.[4] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. Normal persons have a CAG repeat count of between seven and 35 repeats.

The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from base pair 3,113,411 to base pair 3,282,655.

Protein

Function

The function of huntingtin is unclear. It is essential for development, and absence of huntingtin is lethal in mice.[4] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[5] Huntingtin upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.[6] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules.[7][7][8] These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the absorption of materials into a cell.[9][10]

Interactions

Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).[11] Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.[12][13]

Interacting Protein PolyQ length dependence Function
α-adaptin C/HYPJ Yes Endocytosis
Akt/PKB No Kinase
CBP Yes Transcriptional co-activator with acetyltransferase activity
CA150 No Transcriptional activator
CIP4 Yes cdc42-dependent signal transduction
CtBP Yes Transcription factor
FIP2 Not known Cell morphogenesis
Grb2[14] Not known Growth factor receptor binding protein
HAP1 Yes Membrane trafficking
HAP40 Not known Unknown
HIP1 Yes Endocytosis, proapoptotic
HIP14/HYP-H Yes Trafficking, endocytosis
N-CoR Yes Nuclear receptor co-repressor
NF-κB Not known Transcription factor
p53[15] No Transcription factor
PACSIN1[16] Yes Endocytosis, actin cytoskeleton
PSS-95 Yes Synaptic scaffolding protein
RasGAP Not known Ras GTPase activating protein
SH3GL3[17] Yes Endocytosis
SIN3A Yes Transcriptional repressor
Sp1[18] Yes Transcription factor

Huntingtin has also been shown to interact with:

Clinical significance

Main article: Huntington's disease

Huntington's disease (HD) is caused by a mutation in the huntingtin gene, where the CAG repeats more than 36 times and is unstable.[25] These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects.[26] However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39.[27]

Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The presence of these clumps was once thought to play a causal role in Huntington disease.[28] Further research undermined this conclusion by showing the presence of NIIs actually extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.[29] Thus, the likelihood of neuronal death can be predicted by accounting for two factors: (1) the length of CAG repeats in the Huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can thereby be construed as a coping mechanism—as opposed to a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.[30] This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[25]
Repeat count Classification Disease status
<28

| Normal | Unaffected |- | 28–35 | Intermediate | Unaffected |- | 36–40 | Reduced penetrance | +/- Affected |- | >40

 Full penetrance Affected

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.[27]

As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.

References

  1. ↑ PDB 3io4; Kim MW, Chelliah Y, Kim SW, Otwinowski Z, Bezprozvanny I (September 2009). "Secondary structure of Huntingtin amino-terminal region". Structure 17 (9): 1205–12. doi:10.1016/j.str.2009.08.002. PMID 19748341. 
  2. ↑ The Huntington's Disease Collaborative Research Group (March 1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes". Cell 72 (6): 971–83. doi:10.1016/0092-8674(93)90585-E. PMID 8458085. 
  3. ↑ Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC (January 1999). "Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease". Neurology 52 (2): 392–4. PMID 9932964. 
  4. ↑ 4.0 4.1 Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR (June 1995). "Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes". Cell 81 (5): 811–23. doi:10.1016/0092-8674(95)90542-1. PMID 7774020. 
  5. ↑ Cattaneo E, Zuccato C, Tartari M (December 2005). "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews. Neuroscience 6 (12): 919–30. doi:10.1038/nrn1806. PMID 16288298. 
  6. ↑ Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (July 2001). "Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease". Science 293 (5529): 493–8. doi:10.1126/science.1059581. PMID 11408619. 
  7. ↑ 7.0 7.1 Hoffner G, Kahlem P, Djian P (March 2002). "Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease". Journal of Cell Science 115 (Pt 5): 941–8. PMID 11870213. 
  8. ↑ DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA (May 1995). "Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons". Neuron 14 (5): 1075–81. doi:10.1016/0896-6273(95)90346-1. PMID 7748555. 
  9. ↑ Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M (July 1998). "Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways". Experimental Neurology 152 (1): 34–40. doi:10.1006/exnr.1998.6832. PMID 9682010. 
  10. ↑ Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE (August 2001). "The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis". Human Molecular Genetics 10 (17): 1807–17. doi:10.1093/hmg/10.17.1807. PMID 11532990. 
  11. ↑ Harjes P, Wanker EE (August 2003). "The hunt for huntingtin function: interaction partners tell many different stories". Trends in Biochemical Sciences 28 (8): 425–33. doi:10.1016/S0968-0004(03)00168-3. PMID 12932731. 
  12. ↑ Goehler H, Lalowski M, Stelzl U, et al. (September 2004). "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Mol. Cell 15 (6): 853–65. doi:10.1016/j.molcel.2004.09.016. PMID 15383276. Retrieved 2009-04-27. 
  13. ↑ Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, et al. (March 1997). "HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system". Hum. Mol. Genet. 6 (3): 487–95. doi:10.1093/hmg/6.3.487. PMID 9147654. 
  14. ↑ 14.0 14.1 Liu, Y F; Deth R C, Devys D (March 1997). "SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes". J. Biol. Chem. (UNITED STATES) 272 (13): 8121–4. doi:10.1074/jbc.272.13.8121. ISSN 0021-9258. PMID 9079622. 
  15. ↑ Steffan, J S; Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu Y Z, Gohler H, Wanker E E, Bates G P, Housman D E, Thompson L M (June 2000). "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (12): 6763–8. doi:10.1073/pnas.100110097. ISSN 0027-8424. PMC 18731. PMID 10823891. 
  16. ↑ Modregger, January; DiProspero Nicholas A, Charles Vinod, Tagle Danilo A, Plomann Markus (October 2002). "PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains". Hum. Mol. Genet. (England) 11 (21): 2547–58. doi:10.1093/hmg/11.21.2547. ISSN 0964-6906. PMID 12354780. 
  17. ↑ Sittler, A; Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates G P, Lehrach H, Wanker E E (October 1998). "SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates". Mol. Cell (UNITED STATES) 2 (4): 427–36. doi:10.1016/S1097-2765(00)80142-2. ISSN 1097-2765. PMID 9809064. 
  18. ↑ Li, Shi-Hua; Cheng Anna L, Zhou Hui, Lam Suzanne, Rao Manjula, Li He, Li Xiao-Jiang (March 2002). "Interaction of Huntington Disease Protein with Transcriptional Activator Sp1". Mol. Cell. Biol. (United States) 22 (5): 1277–87. doi:10.1128/MCB.22.5.1277-1287.2002. ISSN 0270-7306. PMC 134707. PMID 11839795. 
  19. ↑ Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR (August 1996). "Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme". J. Biol. Chem. 271 (32): 19385–94. doi:10.1074/jbc.271.32.19385. PMID 8702625. 
  20. ↑ Liu YF, Dorow D, Marshall J (June 2000). "Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin". J. Biol. Chem. 275 (25): 19035–40. doi:10.1074/jbc.C000180200. PMID 10801775. 
  21. ↑ Hattula K, Peränen J (2000). "FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis". Curr. Biol. 10 (24): 1603–6. doi:10.1016/S0960-9822(00)00864-2. PMID 11137014. 
  22. ↑ 22.0 22.1 22.2 Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME (September 1998). "Huntingtin interacts with a family of WW domain proteins". Hum. Mol. Genet. 7 (9): 1463–74. doi:10.1093/hmg/7.9.1463. PMID 9700202. 
  23. ↑ Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Néri C (March 2003). "Cdc42-interacting protein 4 binds to huntingtin: Neuropathologic and biological evidence for a role in Huntington's disease". Proc. Natl. Acad. Sci. U.S.A. 100 (5): 2712–7. doi:10.1073/pnas.0437967100. PMC 151406. PMID 12604778. 
  24. ↑ Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, Yanai A, Gutekunst CA, Leavitt BR, Yi H, Fichter K, Gan L, McCutcheon K, Chopra V, Michel J, Hersch SM, Ikeda JE, Hayden MR (November 2002). "HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis". Hum. Mol. Genet. 11 (23): 2815–28. doi:10.1093/hmg/11.23.2815. PMID 12393793. 
  25. ↑ 25.0 25.1 Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289. 
  26. ↑ Huntington's Disease Collaborative Research Group (1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes". Cell 72 (6): 971–983. doi:10.1016/0092-8674(93)90585-E. PMID 8458085. 
  27. ↑ 27.0 27.1 Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B, Goldberg YP, Haddad BR, Richards F, Sillence D, Greenberg CR, Ives E, Van den Engh G, Hughes MR, Hayden MR (February 1997). "Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses". Human Molecular Genetics 6 (2): 301–9. doi:10.1093/hmg/6.2.301. PMID 9063751. 
  28. ↑ Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (August 1997). "Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation". Cell 90 (3): 537–48. doi:10.1016/S0092-8674(00)80513-9. PMID 9267033. 
  29. ↑ Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004). "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death". Nature 431 (7010): 805–810. doi:10.1038/nature02998. PMID 15483602. 
  30. ↑ Orr HT (October 2004). "Neurodegenerative disease: neuron protection agency". Nature 431 (7010): 747–8. doi:10.1038/431747a. PMID 15483586. 

Further reading

External links

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