Huntingtin
From Proteopedia
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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 <ref>DOI 10.1073/pnas.0610628104</ref>. Furthermore, HTT has been shown to localize to spindle poles during mitosis, regulating spindle orientation in mouse neuronal cells<ref>DOI 10.1016/j.neuron.2010.06.027</ref>. 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 <ref>DOI 10.1007/s11062-013-9341-1</ref> | 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 <ref>DOI 10.1073/pnas.0610628104</ref>. Furthermore, HTT has been shown to localize to spindle poles during mitosis, regulating spindle orientation in mouse neuronal cells<ref>DOI 10.1016/j.neuron.2010.06.027</ref>. 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 <ref>DOI 10.1007/s11062-013-9341-1</ref> | ||
| + | '''Huntingtin Protein and Autophagy''' | ||
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==Structure== | ==Structure== | ||
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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 <ref>DOI 10.1074/jbc.M511007200</ref>. The presence of HEAT repeats enables HTT to participate in endocytosis-related trafficking, as clathrin and COPI (coat protein complex I) coatomer contain HEAT repeats as well <ref>DOI 10.1101/gr.147400</ref>. | 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 <ref>DOI 10.1074/jbc.M511007200</ref>. The presence of HEAT repeats enables HTT to participate in endocytosis-related trafficking, as clathrin and COPI (coat protein complex I) coatomer contain HEAT repeats as well <ref>DOI 10.1101/gr.147400</ref>. | ||
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== Pathology == | == Pathology == | ||
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The general consensus is that the toxicity originates from the gain of function of mHTT, as the polyQ solely could still stretch and let to the development of neurological symptoms in mouse models <ref>DOI 10.1038/ng0696-196</ref><ref>DOI 10.1016/s0092-8674(00)81369-0</ref><ref>10.1016/s0092-8674(00)80464-x</ref>. However, the contribution of loss of function of the wild-type HTT cannot be abandoned, as wild-type HTT inactivation or deletion also leads to neurodegeneration <ref>DOI 10.1016/s0006-8993(98)01312-2</ref><ref>DOI 10.1038/81593</ref>. | The general consensus is that the toxicity originates from the gain of function of mHTT, as the polyQ solely could still stretch and let to the development of neurological symptoms in mouse models <ref>DOI 10.1038/ng0696-196</ref><ref>DOI 10.1016/s0092-8674(00)81369-0</ref><ref>10.1016/s0092-8674(00)80464-x</ref>. However, the contribution of loss of function of the wild-type HTT cannot be abandoned, as wild-type HTT inactivation or deletion also leads to neurodegeneration <ref>DOI 10.1016/s0006-8993(98)01312-2</ref><ref>DOI 10.1038/81593</ref>. | ||
As mentioned above, patients with mHTT develop HD. HD is an autosomal dominant neurodegenerative disorder characterized by behavioral, cognitive and motor dysfunctions. Although HD mostly affects middle-aged people, the age of onset is inversely correlated with the length of the polyQ tract. Very large expansion can even lead to juvenile and in rare cases infantile forms of the disease <ref>DOI 10.1016/j.nbd.2015.09.008</ref>. | As mentioned above, patients with mHTT develop HD. HD is an autosomal dominant neurodegenerative disorder characterized by behavioral, cognitive and motor dysfunctions. Although HD mostly affects middle-aged people, the age of onset is inversely correlated with the length of the polyQ tract. Very large expansion can even lead to juvenile and in rare cases infantile forms of the disease <ref>DOI 10.1016/j.nbd.2015.09.008</ref>. | ||
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| - | '''Huntingtin Protein Impairs Ubiquitin-Proteasome System and Autophagy''' | ||
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| - | There are two major pathways that secure the degradation of intracellular proteins. The ubiquitin-proteasome system, which serve to degrade wild-type HTT, and autophagy, which seems to be more important for the degradation of the expanded mutant forms. <ref>DOI 10.1101/cshperspect.a024240.</ref> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 08:16, 25 April 2020
Huntingtin Protein
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