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The COOH-terminal domain of huntingtin interacts with RhoGEF kalirin and modulates cell survival
Human huntingtin (Htt) contains 3144 amino acids and has an expanded polyglutamine region near the NH(2)-terminus in patients with Huntington’s disease. While numerous binding partners have been identified to NH(2)-terminal Htt, fewer proteins are known to interact with C-terminal domains of Htt. He...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964228/ https://www.ncbi.nlm.nih.gov/pubmed/29789657 http://dx.doi.org/10.1038/s41598-018-26255-1 |
Sumario: | Human huntingtin (Htt) contains 3144 amino acids and has an expanded polyglutamine region near the NH(2)-terminus in patients with Huntington’s disease. While numerous binding partners have been identified to NH(2)-terminal Htt, fewer proteins are known to interact with C-terminal domains of Htt. Here we report that kalirin, a Rac1 activator, is a binding partner to C-terminal Htt. Kalirin and Htt co-precipitated from mouse brain endosomes and co-localized at puncta in NRK and immortalized striatal cells and primary cortical neurons. We mapped the interaction domains to kalirin674-1272 and Htt2568-3144 and determined that the interaction between kalirin and Htt was independent of HAP1, a known interactor for Htt and kalirin. Kalirin precipitated with mutant Htt was more abundant than with wild-type Htt and had a reduced capacity to activate Rac1 when mutant Htt was present. Expression of Htt2568-3144 caused cytotoxicity, partially rescued by co-expressing kalirin674-1272 but not other regions of kalirin. Our study suggests that the interaction of kalirin with the C-terminal region of Htt influences the function of kalirin and modulates the cytotoxicity induced by C-terminal Htt. |
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