Huntingtin protein

Huntingtin protein

protein
Name = Huntingtin


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Symbol = Htt
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Chromosome = 4
Arm = p16.3
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Huntingtin (Htt) is the protein coded by the gene, huntingtin, identified in 1993. [cite journal |author= |title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group |journal=Cell |volume=72 |issue=6 |pages=971–83 |year=1993 |pmid=8458085|doi=10.1016/0092-8674(93)90585-E] It is variable in its structure as there are many polymorphisms of the gene which 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 between 36-155 glutamine residues. Huntingtin has a predicted mass of ~350kDa, however, this varies and is largely dependent on the number of glutamine residues in the protein. Normal huntingtin is generally accepted to be 3144 amino acids in size.

Function

The function of Huntingtin is unclear. It is essential for development and absence of huntingtin is lethal in mice. cite journal | author=Nasir J, Floresco S, et al | title=Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes | journal =Cell | volume = 81 | pages=811–823 | date=1995 | doi=10.1016/0092-8674(95)90542-1] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.cite journal | author=Cattaneo E, Zuccato C, Tartari M | title=Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews Neuroscience | volume = 6 | pages= 919–930 | date=2005 Dec | doi=10.1038/nrn1806] It has however been experimentally demonstrated that Huntingtin acts as a transcription factor in upregulating the expression of Brain Derived Neurotrophic Factor (BDNF). In the deficient protein, there is suppression of this transcription regulatory function of Huntingtin and hence underexpression of BDNF.cite journal | author=Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, et al | title=Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease | journal=Science | date=2001 Jul 20 | volume = 293| issue=5529 | pages=445–6] From immunohistochemistry, electron microscopy, subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated with vesicles and microtubules.cite journal | author=Hoffner G, Kahlem P, Djian P | title=Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with β-tubulin: relevance to Huntington's disease | journal= J Cell Sci | volume=115 | pages=941–948 | date=2002] cite journal | author=DiFiglia M, et al. | title = Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons | journal=Neuron | volume=14 | pages = 1075–1081 | date=1995 | doi = 10.1016/0896-6273(95)90346-1] .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 HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell. [cite journal |author=Velier J, Kim M, Schwarz C, "et al." |title=Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways |journal=Exp. Neurol. |volume=152 |issue=1 |pages=34–40 |year=1998 |pmid=9682010 |doi=10.1006/exnr.1998.6832] [cite journal |author=Waelter S, Scherzinger E, Hasenbank R, "et al." |title=The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis |journal=Hum. Mol. Genet. |volume=10 |issue=17 |pages=1807–17 |year=2001 |pmid=11532990| doi = 10.1093/hmg/10.17.1807 ]

Interactions

Huntingtin has been found to interact with a number of proteins,such as Huntingtin-associated protein 1 (HAP1) and Huntingtin Interacting Protein 1 (HIP1).cite journal | author=Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, et al | title=HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system | journal = Hum. Mol. Genet. | date=1997 Mar | volume = 6 | issue = 3 | pages = 487–95 | doi=10.1093/hmg/6.3.487 ] .

[Harjes, P. and E. E. Wanker (2003). "The hunt for huntingtin function: interaction partners tell many different stories." Trends Biochem Sci 28(8): 425-33.]

Abnormal huntingtin (mHtt)

The key sequence which is found in Huntington's disease (HD) 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.cite journal | author=Huntington's Disease Collaborative Research Group | title=A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes | journal = Cell | volume =72 | pages=971–983 | date=1993 | doi=10.1016/0092-8674(93)90585-E] However, 36 or more residues produce an erroneous form of Htt, mHtt (standing for mutant Htt). Reduced penetrance is found in counts 36-39. [Chong, S.S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., Goldberg, Y.P., Haddad, B.R., Richards, F., Sillence, D., Greenberg, C.R., Ives, E., Van den Engh, G., Hughes, M.R., and Hayden, M.R. (1997). Contribution of DNA sequence and CAG size to mutation frquences of intermediate alleles for Huntington Disease: Evidence from single sperm analyses. Human Molecular Genetics 6:302-309]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=MacDonald ME, Novelletto A, Lin C, "et al." |title=The Huntington's disease candidate region exhibits many different haplotypes. |journal=Nat. Genet. |volume=1 |issue= 2 |pages= 99–103 |year= 1993 |pmid= 1302016 |doi= 10.1038/ng0592-99
*cite journal | author=Jones AL |title=The localization and interactions of huntingtin. |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=354 |issue= 1386 |pages= 1021–7 |year= 1999 |pmid= 10434301 |doi= 10.1098/rstb.1999.0454
*cite journal | author=Young AB |title=Huntingtin in health and disease. |journal=J. Clin. Invest. |volume=111 |issue= 3 |pages= 299–302 |year= 2003 |pmid= 12569151 |doi=
*cite journal | author=Rangone H, Humbert S, Saudou F |title=Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic? |journal=Pathol. Biol. |volume=52 |issue= 6 |pages= 338–42 |year= 2004 |pmid= 15261377 |doi= 10.1016/j.patbio.2003.06.004
*cite journal | author=Li SH, Li XJ |title=Huntingtin and its role in neuronal degeneration. |journal=The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry |volume=10 |issue= 5 |pages= 467–75 |year= 2005 |pmid= 15359012 |doi= 10.1177/1073858404266777
*cite journal | author=Myers RH |title=Huntington's disease genetics. |journal=NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics |volume=1 |issue= 2 |pages= 255–62 |year= 2005 |pmid= 15717026 |doi=

External links

*
* [http://www.stanford.edu/group/hopes/causes/huntprot/p1.html The Huntingtin Protein and Protein Aggregation] at [http://hopes.stanford.edu/ hopes.stanford.edu]


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