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The COOH-terminal domain of huntingtin interacts with RhoGEF kalirin and modulates cell survival
- Source :
- Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group UK, 2018.
-
Abstract
- Human huntingtin (Htt) contains 3144 amino acids and has an expanded polyglutamine region near the NH2-terminus in patients with Huntington’s disease. While numerous binding partners have been identified to NH2-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.
- Subjects :
- 0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Huntingtin
Endosome
Cell Survival
animal diseases
Mutant
lcsh:Medicine
RAC1
Mice, Transgenic
Protein Serine-Threonine Kinases
Article
03 medical and health sciences
Mice
mental disorders
Animals
Guanine Nucleotide Exchange Factors
Humans
Protein Interaction Domains and Motifs
lcsh:Science
Cytotoxicity
Cell survival
Cells, Cultured
chemistry.chemical_classification
Huntingtin Protein
Multidisciplinary
Activator (genetics)
lcsh:R
Cell biology
Amino acid
nervous system diseases
030104 developmental biology
chemistry
nervous system
MCF-7 Cells
lcsh:Q
Rho Guanine Nucleotide Exchange Factors
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 20452322 and 25683144
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....b04a617e351264bfb08002bf8b50b784