Oral Presentation The 45th Lorne Conference on Protein Structure and Function 2020

Structural basis of the zinc-induced cytoplasmic accumulation of the Alzheimer’s disease- and ALS-linked RNA-binding protein SFPQ (#44)

Jie Huang 1 , Mitchell Ringuet 2 , Andrew E. Whitten 3 , Sofia Caria 1 4 , Yee Wa Lim 1 , Rahul Badhan 1 , Victor Anggono 2 , Mihwa Lee 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
  3. Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW, Australia
  4. SAXS/WAXS, Australian Synchrotron, ANSTO, Clayton, VIC, Australia

SFPQ is an abundant nuclear protein implicated in many aspects of RNA biogenesis. Importantly, nuclear depletion and cytoplasmic accumulation of SFPQ has been linked to neuropathological conditions such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Here we report the structural basis of cytoplasmic accumulation of SFPQ induced by zinc. The crystal structure in complex with zinc reveals the intermolecular interactions of SFPQ mediated by zinc, resulting in infinite polymerisation of SFPQ. As anticipated, the application of zinc to primary cortical neurons induced cytoplasmic accumulation and aggregation of SFPQ. Mutagenesis on the three histidine residues coordinating zinc resulted in a significant reduction in zinc-binding affinity in vitro and zinc-induced cytoplasmic aggregation of SFPQ in cultured neurons. Taken together, we propose that dysregulation of zinc in neuronal cells may represent a potential mechanism that leads to an imbalance in the nucleocytoplasmic distribution of SFPQ, an emerging hallmark of neurodegenerative diseases including AD and ALS. This study, to our best knowledge, is the first example presenting the structural basis of the Zn-induced aggregation of RNA-binding protein implicated in neurological diseases.