Huntingtin (Htt) is a human protein encoded by the HTT gene, also known as IT15 ("interesting transcript 15"). Pathogenic expansions in HTT (disease-causing repeat length increases) cause Huntington's disease (HD), and the protein has also been implicated in mechanisms of long-term memory storage. HTT is expressed in many tissues, with the highest levels in the brain. Expression is developmentally regulated and required for embryogenesis. Huntingtin normally consists of 3,144 amino acids and has a predicted mass of ~350 kDa, depending on the length of its polyglutamine tract. Polymorphisms in HTT alter the number of glutamine residues: the wild-type allele encodes 6–35 repeats, whereas pathogenic expansions in HD exceed 36, with severe juvenile cases reaching ~250 repeats. The name huntingtin reflects this association with disease; IT15 was its earlier designation. The molecular functions of huntingtin are not fully defined, but the protein is essential for neuronal survival and development. It is thought to contribute to intracellular signaling pathways, axonal transport, and vesicle trafficking, as well as to mediate protein–protein interactions. Huntingtin has also been shown to exert protective effects against apoptosis. Experimental disruption of HTT in model organisms results in embryonic lethality, underscoring its critical role in development. Expanded polyglutamine tracts in huntingtin cause toxic gain-of-function effects leading to Huntington's disease, an autosomal dominant neurodegenerative disease. The pathogenic protein aggregates in neurons, disrupting cellular processes and ultimately causing cell death.
Gene The 5'-end (five prime end) of the HTT 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. The usual CAG repeat count is between seven and 35 repeats. 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.
Structure The Huntingtin (HTT) protein is a large, predominantly α-helical molecule composed of 3,144 amino acids and weighing approximately 348kDa in its canonical form. Its structure is organized into three major domains: the amino-terminal domain, the carboxy-terminal domain, and a smaller bridge domain that connects the two. Both the amino- and carboxy-terminal regions are characterized by multiple HEAT repeats (named for Huntingtin, Elongation factor 3, Protein phosphatase 2A, and lipid kinase TOR), which are arranged in a solenoid or superhelical fashion and play a crucial role in mediating protein-protein interactions. The bridge domain contains various types of tandem repeats and helps maintain the structural connection between the larger domains. The highly variable N-terminal segment of huntingtin contains the polyglutamine (polyQ) tract—expanded in Huntington's disease—which is often intrinsically disordered and not fully resolved in high-resolution structures. Huntingtin's flexible, extended architecture is stabilized when complexed with HAP40, a partner protein, allowing the protein to function as a scaffold and interaction hub in the cell. 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.
Function The function of huntingtin (Htt) is not well understood but it is involved in axonal transport. Huntingtin is essential for development, and its absence is lethal in mice. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents. 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. From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules. 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 trafficking of materials into a cell. Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.
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). 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.
Huntingtin has also been shown to interact with:
Clinical significance
Huntington's disease
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