Huntingtin: Difference between revisions
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This page was created as a homework for the subject, Structural biology of the cell (Science faculty of Charles Unicersity in Prague). None of the pictures and schemes are mine. | This page was created as a homework for the subject, Structural biology of the cell (Science faculty of Charles Unicersity in Prague). None of the pictures and schemes are mine. | ||
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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 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>. | 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>. | 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>. | ||
== Structural highlights == | |||
The huntingtin N-terminal assumes a helical conformation (residues 3-11) followed by an extended conformation (residues 12-17). It forms <scene name='74/749958/Cv/3'>interactions with the antibody heavy and light chains</scene><ref>PMID:25861763</ref>. | |||
== 3D Structures of huntingtin == | == 3D Structures of huntingtin == | ||
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | ||
[[4rav]] – hHTT N-terminal + antibody | [[6rmh]], [[6yej]] – hHTT – human - Cryo EM <br /> | ||
[[4rav]] – hHTT N-terminal + antibody<br /> | |||
[[2ld0]], [[2ld2]], [[6n8c]] – hHTT N-terminal - NMR<br /> | [[2ld0]], [[2ld2]], [[6n8c]] – hHTT N-terminal - NMR<br /> | ||
[[3io4]], [[3io6]], [[3ior]], [[3iot]], [[3iou]], [[3iov]], [[3iow]] – hHTT N-terminal/MBP<br /> | [[3io4]], [[3io6]], [[3ior]], [[3iot]], [[3iou]], [[3iov]], [[3iow]] – hHTT N-terminal/MBP<br /> | ||
[[4fe8]], [[4feb]], [[4fec]], [[4fed]] – hHTT residues 1-164 (mutant)/MBP<br /> | [[4fe8]], [[4feb]], [[4fec]], [[4fed]] – hHTT residues 1-164 (mutant)/MBP<br /> | ||
[[6rmh]] – hHTT – Cryo EM <br /> | [[6rmh]] – hHTT – Cryo EM <br /> | ||
[[6ez8]], [[ | [[6ez8]] – hHTT + CPG island protein – Cryo EM <br /> | ||
[[6x9o]], [[7dxj]], [[7dxk]], [[8vlx]], [[8w15]], [[9pmw]], [[9pn0]] – hHTT + HAP40 – Cryo EM <br /> | |||
[[8sah]] – hHTT C-HEAT domain 2093-3136 + HAP40 – Cryo EM <br /> | |||
[[8yae]], [[8yao]] – hHTT + actin – Cryo EM <br /> | |||
== References == | == References == | ||
<references/> | <references/> | ||
[[Category:Topic Page]] | |||
