Huntingtin: Difference between revisions

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 as well as dysfunctional organelles <ref>DOI 10.1101/cshperspect.a024240</ref>. Wild-type HTT seems to act as a scaffold for many parts of the autophagic machinery. The C-terminal part of HTT was found to have similar structure to Atg11, a yeast scaffolding protein associated with autophagy. Moreover, HTT was shown to interact with human homolog proteins, such as ULK1 (Unc-51 like autophagy activating kinase; homolog of yeast Atg1) and SQSTM1/p62 (homolog of yeast Atg19), which interact with Atg11 <ref>DOI 10.1073/pnas.1420103111</ref>. In mammals, the induction of autophagy depends on the ULK1-Atg13-FIP2000 complex. This complex is for most of the time inhibited by mTORC1-mediated phosphorylation. Furthermore, an exclusive complex with HTT can be formed. This complex does not lead to the inhibition of ULK1 and promotes the initiation of autophagy <ref>DOI 10.1080/15548627.2015.1039219</ref>. However, ULK1 has reduced affinity to mHTT and thereby reamins more inactive and bound to mTOR <ref>DOI 10.1101/330001</ref>.

SQSTM1/p62 is an autophagy adaptor protein that binds cargo tagged with polyubiquitin chains to autophagosomes via the interaction with LC3-II. Although autophagosomes seem to be formed at a higher rate in HD models, HD autophagosomes cannot sequester the cargo properly and leads to the accumulation of dysfuncitonal proteins and organelles <ref>DOI 10.1038/nn.2528</ref>.

== 3D Structures of huntingtin ==