Dagmar E Ehrnhoefer1, Niels H Skotte2, Jeanette Reinshagen3, Xiaofan Qiu2, Björn Windshügel3, Priyadarshini Jaishankar4, Safia Ladha2, Olga Petina5, Mehdi Khankischpur5, Yen T N Nguyen2, Nicholas S Caron2, Adelia Razeto3, Matthias Meyer Zu Rheda3, Yu Deng2, Khuong T Huynh2, Ilka Wittig6, Philip Gribbon3, Adam R Renslo4, Detlef Geffken5, Sheraz Gul3, Michael R Hayden2. 1. Centre for Molecular Medicine and Therapeutics (CMMT), Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Electronic address: ehrnhoefer@bio.mx. 2. Centre for Molecular Medicine and Therapeutics (CMMT), Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. 3. Fraunhofer Institute for Molecular Biology and Applied Ecology IME - ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany. 4. Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA. 5. University of Hamburg, Institut für Pharmazie, Bundesstraße 45, 20146 Hamburg, Germany. 6. Functional Proteomics, ZBC, Faculty of Medicine, Goethe University, Theodor-Stern-Kai 7/Haus 26, 60590 Frankfurt, Germany.
Abstract
Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.
Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonsn class="Gene">trated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis.
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