| Huntingtin (HTT) | |
|---|---|
| Gene | HTT |
| UniProt | P42857 |
| PDB | 3IO4, 6ZFR |
| Mol. Weight | ~350 kDa (full-length) |
| Localization | Cytoplasm, nucleus, synapses |
| Family | Huntingtin protein family |
| Diseases | Huntington's Disease |
Huntingtin (Htt) Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Huntingtin (HTT) is a massive 3,144-amino acid protein encoded by the HTT gene that is central to the pathogenesis of Huntington's disease (HD), an autosomal dominant neurodegenerative disorder[1]. Wild-type huntingtin is essential for normal neuronal function, while mutant huntingtin with expanded polyglutamine (polyQ) tracts becomes toxic and leads to progressive neurodegeneration in the striatum and cortex[2].
Huntingtin is one of the largest proteins in the human proteome and participates in numerous cellular functions including vesicle trafficking, transcription regulation, mitochondrial dynamics, and synaptic transmission. The discovery that CAG repeat expansion in HTT causes HD has made this protein a major therapeutic target[3].
Huntingtin is a modular protein with multiple functional domains:
Contains the polyglutamine (polyQ) tract whose length determines disease onset:
Huntingtin contains approximately 36 HEAT repeats - helical repeats that mediate protein-protein interactions. These repeats form a superhelical structure involved in binding various partner proteins.
Multiple caspase (especially caspase-6) cleavage sites in the N-terminal region generate toxic fragments in disease states.
Located near the C-terminus, involved in nuclear import of huntingtin fragments.
Located downstream of the polyQ tract, involved in protein interactions via SH3 domains.
Wild-type huntingtin is ubiquitously expressed and essential for development. Key normal functions include:
Mutant huntingtin (mHTT) with expanded polyQ repeats causes HD through multiple mechanisms:
The striatum (caudate nucleus and putamen) and cortex are most affected due to:
The study of Huntingtin (Htt) Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
The Huntington's Disease Collaborative Research Project. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993):971-983. DOI:;72(610.1016/0092-8674(93)90585-E ↩︎
MacDonald ME, Ambrose CM, Duyao MP, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983. DOI:10.1016/0092-8674(93)90585-E ↩︎
Gusella JF, MacDonald ME. Huntington's disease: seeing the pathogenic process through a genetic lens. Trends Biochem Sci. 2006;31(9):533-540. DOI:10.1016/j.tibs.2006.06.009 ↩︎