Huntingtin

Huntingtin (HTT) is a large (350 kDa) protein essential for embryonic development and is involved in a variety of cellular functions, such as vesicular transport, endocytosis, transcription regulation and autophagy. Mutation in the associated gene — IT15 — results in an expansion of the polyQ tract found within the N-terminal region of the perspective protein. Such pathological growth, which surpasses the treshold of 36 glutamine residues, may lead to the development of Huntington disease (HD). The mutation becomes fully penetrant at ≥40 glutamine residues ^[1]. Mutant huntingtin (mHTT) is prone to aggregation. Yet, despite its ubiquitous expression, mHTT affects primarily the GABAergic medium spiny neurons of striatum and to a lesser extent the neurons of cerebral cortex ^[2].

Function

Since the discovery of HTT and its relevance to HD, efforts have been made to understand the physiological functions of wild-type huntingtin. However, an integrative understanding of its biological functions is still lacking. Many studies suggest that HTT is essential for cell survival and thereby its loss of function caused by the mutation is source for the neurodegeneration. Although it does, up to a certain degree, add to the disease phenotype, it is now generally believed that the main source of the disease is not the loss of its physiological functions, but the gain of function associated with the polyQ expansion.

Huntingtin and Embryonic Development

The crucial role of HTT for embryonic development has been shown using mouse knock-out (KO) models, in which homozygous KO mice die at day 8.5 and don't emerge the nervous system. ^[3] Furthermore, HTT was shown to play a key role in neurulation homotypic interactions of neuroepithelial cells, thereby providing more evidence on its importace for development of the nervous system.

Huntingtin and Transcription Regulation

HTT is mostly cytoplasmic. However, it can be aslo observed in the nucleus, as HTT comprises nuclear localization sequence in its NH2 terminus ^[4]. Its nuclear localization implies for its role in transcription regulation. An example of a well described target gene of HTT-mediated transcription regulation is the brain derived nerve growth factor (BDNF) ^[5]. However, there are more transcription factors described to interact with mHTT, as their interaction may lead to transcription dysregulation. Thanks to its abnormal structure, mHTT supresses the expression of PGC1-α — a transcription factor responsible for the regulation of many mitochondrial genes ^[6].

Huntingtin as a Scaffold Protein

Wild-type HTT is well known for its scaffolding function. It interacts with β-tubulin and binds to microtubules. Besides, it interacts with the dynein/dynactin complex, thereby regulating vesicular transport ^[7]. Furthermore, HTT has been shown to localize to spindle poles during mitosis, regulating spindle orientation in mouse neuronal cells^[8]. On the other hand, the abnormal scaffolding function for molecular motors operated via mHTT results in abrupted axonal transport. That leads to inefficient distribution of mitochondria within nerve cells, causing low ^[9]

Structure

HTT is a 3144 amino acids comprising protein, which possesses the polyglutamine chain at the amino-terminal region. It also contains multiple consesnsus sequences called HEAT (huntingtin, elongation factor 3, protein phosphatase 2A, and TOR1 (target of rapamycin)) repeats. These HEAT repeats are very important for protein-protein interactions, of which HTT has plentiful. HEAT repeats consist of helix-turn-helix motifs, which are packed into a compact form of a superhelix hydrophobic core able to resist dissociation upon proteolytic cleavage ^[10]. The presence of HEAT repeats enables HTT to participate in endocytosis-related trafficking thanks to clathrin and COPI (coat protein complex I) coatomer containing HEAT repeats as well ^[11].

Disease

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