- Huntingtin protein
protein
Name = Huntingtin
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Symbol = Htt
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Chromosome = 4
Arm = p16.3
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LocusSupplementaryData =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 manypolymorphisms of the gene which can lead to variable numbers ofglutamine residues present in the protein. In itswild-type (normal) form, it contains 6-35glutamine residues, however, in individuals affected byHuntington's Disease (anautosomal 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 atranscription 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] Fromimmunohistochemistry ,electron microscopy ,subcellular fractionation studies of the molecule, it has been found that Huntingtin is primarily associated withvesicles andmicrotubules .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 ofmitochondria . The Htt protein is involved in vesicle trafficking as it interacts with HIT1, aclathrin binding protein, to mediateendocytosis , 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 asHuntingtin-associated protein 1 (HAP1) andHuntingtin 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)
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