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The polyglutamine expansion at the n-terminal of Huntingtin protein modulates the dynamic configuration and phosphorylation of the c-terminal HEAT domain

DOI: 10.1016/j.str.2020.06.008 DOI Help

Authors: Taeyang Jung (Korea Advanced Institute of Science and Technology (KAIST); KTH Royal Institute of Technology; Karolinska Institutet) , Baehyun Shin (Massachusetts General Hospital; Harvard Medical School) , Giorgio Tamo (Ecole Polytechnique Fédérale de Lausanne (EPFL)) , Hyeongju Kim (Korea Advanced Institute of Science and Technology (KAIST)) , Ravi Vijayvargia (Massachusetts General Hospital; Harvard Medical School) , Alexander Leitner (ETH Zürich) , Maria J. Marcaida (Ecole Polytechnique Fédérale de Lausanne (EPFL)) , Juan Astorga-Wells (Karolinska Institutet) , Roy Jung (Massachusetts General Hospital; Harvard Medical School) , Ruedi Aebersold (ETH Zürich; University of Zürich) , Matteo Dal Peraro (Ecole Polytechnique Fédérale de Lausanne (EPFL)) , Hans Hebert (KTH Royal Institute of Technology; Karolinska Institutet) , Ihn Sik Seong (Massachusetts General Hospital; Harvard Medical School) , Ji-Joon Song (Korea Advanced Institute of Science and Technology (KAIST))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: July 2020

Abstract: The polyQ expansion in huntingtin protein (HTT) is the prime cause of Huntington's disease (HD). The recent cryoelectron microscopy (cryo-EM) structure of HTT-HAP40 complex provided the structural information on its HEAT-repeat domains. Here, we present analyses of the impact of polyQ length on the structure and function of HTT via an integrative structural and biochemical approach. The cryo-EM analysis of normal (Q23) and disease (Q78) type HTTs shows that the structures of apo HTTs significantly differ from the structure of HTT in a HAP40 complex and that the polyQ expansion induces global structural changes in the relative movements among the HTT domains. In addition, we show that the polyQ expansion alters the phosphorylation pattern across HTT and that Ser2116 phosphorylation in turn affects the global structure and function of HTT. These results provide a molecular basis for the effect of the polyQ segment on HTT structure and activity, which may be important for HTT pathology.

Journal Keywords: cryo-EM; conformational change; integrative structural approach; post-translational modification

Diamond Keywords: Huntington's Disease (HD)

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: BM29 at ESRF

Added On: 23/07/2020 10:45

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Neurodegenerative Diseases Neurology Non-Communicable Diseases Structural biology

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)