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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Jiang, Haibing Poirier, Michelle A. D'ambola, James Chighladze, Ekaterine Liang, Yideng Hirschhorn, Ricky R. Gucek, Marjan Hayden, Michael R. Ross, Christopher A. Cole, Robert N. Graham, Rona Ratovitski, Tamara Hou, Zhipeng Waldron, Elaine |
| Description | Author Affiliation: Ratovitski T ( Division of Neurobiology, Department of Psychiatry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. tratovi1@jhmi.edu) |
| Abstract | Huntingtin proteolysis is implicated in Huntington disease pathogenesis, yet, the nature of huntingtin toxic fragments remains unclear. Huntingtin undergoes proteolysis by calpains and caspases within an N-terminal region between amino acids 460 and 600. We have focused on proteolytic steps producing shorter N-terminal fragments, which we term cp-1 and cp-2 (distinct from previously described cp-A/cp-B). We used HEK293 cells to express the first 511 residues of huntingtin and further define the cp-1 and cp-2 cleavage sites. Based on epitope mapping with huntingtin-specific antibodies, we found that cp-1 cleavage occurs between residues 81 and 129 of huntingtin. Affinity and size exclusion chromatography were used to further purify huntingtin cleavage products and enrich for the cp-1/cp-2 fragments. Using mass spectrometry, we found that the cp-2 fragment is generated by cleavage of huntingtin at position Arg(167). This site was confirmed by deletion analysis and specific detection with a custom-generated cp-2 site neo-epitope antibody. Furthermore, alterations of this cleavage site resulted in a decrease in toxicity and an increase in aggregation of huntingtin in neuronal cells. These data suggest that cleavage of huntingtin at residue Arg(167) may mediate mutant huntingtin toxicity in Huntington disease. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 16 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-04-17 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Nerve Tissue Proteins Metabolism Toxicity Neurons Nuclear Proteins Peptide Fragments Amino Acid Sequence Animals Cell Line Huntington Disease Pathology Molecular Sequence Data Genetics Cytology Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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