Product Code Database
Huntingtin (Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutation HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.
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, the polymorphic locus contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), the polymorphic locus contains more than 36 glutamine residues (highest reported repeat length is about 250). 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 . Within cells, huntingtin may or may not be involved in signaling, transporting materials, binding proteins and other structures, and protecting against apoptosis, a form of programmed cell death. The huntingtin protein is required for normal development before birth. It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.
In recent years, multiple research groups have managed to resolve the 3D structure of full-size HTT using cryogenic electron microscopy cryoEM. This revealed the 3D architecture of the various helical HEAT repeat domains that make up the protein's native fold, as illustrated in the figure to right. However, up to 25% of the protein chain was not visible in the structure, due to flexibility. This notably included the N-terminal region affected by mutations in Huntington's disease, as discussed below.
The HTT gene is located on the short arm (p) of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.
| 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 |
| Optineurin | Not known | Cell morphogenesis |
| Grb2 | Not known | Growth factor receptor binding protein |
| HAP1 | Yes | Membrane trafficking |
| HAP40 ( F8A1, F8A2, F8A3) | 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 | No | Transcription factor |
| PACSIN1 | Yes | Endocytosis, actin cytoskeleton |
| DLG4 (PSD-95) | Yes | Postsynaptic Density 95 |
| RASA1 (RasGAP) | Not known | Ras GTPase activating protein |
| SH3GL3 | Yes | Endocytosis |
| SIN3A | Yes | Transcriptional repressor |
| Sp1 | Yes | Transcription factor |
Huntingtin has also been shown to interact with:
Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein. 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. However, 36 or more residues produce an erroneous mutant form of Htt, (mHtt). Reduced penetrance is found in counts 36–39.
N-terminal fragments of mHtt have been discovered in Huntington's disease patients. These fragments can be generated by protease enzymes that cut this elongated protein into fragments. Moreover, recent research has identified aberrant splicing to affect the mutant gene products, yielding fragments that coincide with the first exon of the protein. These protein fragments are observed to form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The characteristic presence of these clumps in patients was thought to contribute to the development of Huntington disease. However, later research raised questions about the role of the inclusions (clumps) by showing the presence of visible NIIs extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons. One confounding factor is that different types of aggregates are now recognised to be formed by the mutant protein, including protein deposits that are too small to be recognised as visible deposits in the above-mentioned studies. The likelihood of neuronal death remains difficult to predict. Likely multiple factors are important, including: (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 be helpful as a coping mechanism—and not simply a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin. 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). Further, it is possible the pathogenic mechanism lay more with the RNA transcripts and their potential CAG repeats to exhibit RNAi than with the actual huntingtin protein itself.
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.
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.
In the pathogenesis of the disease, there is further somatic expansion of CAG repeats. It takes decades to reach 80 repeats, then years to reach 150 repeats. Beyond 150, cellular toxicity start to manifest. Over months, the neuron slowly loses its cell identity until cell death pathways are activated.
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