Defining the Kv2.1–Syntaxin Molecular Interaction Identifies a First-In-Class Small Molecule Neuroprotectant
Defining the Kv2.1–syntaxin molecular interaction identifies a first-in-class small molecule neuroprotectant Chung-Yang Yeha,b,1, Zhaofeng Yec,d,1, Aubin Moutale, Shivani Gaura,b, Amanda M. Hentonf,g, Stylianos Kouvarosf,g, Jami L. Salomana, Karen A. Hartnett-Scotta,b, Thanos Tzounopoulosa,f,g, Rajesh Khannae, Elias Aizenmana,b,g,2, and Carlos J. Camachoc,2 aDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; bPittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; cDepartment of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; dSchool of Medicine, Tsinghua University, Beijing 100871, China; eDepartment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724; fDepartment of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and gPittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved June 19, 2019 (received for review February 27, 2019) + The neuronal cell death-promoting loss of cytoplasmic K follow- (13). The Kv2.1-dependent cell death pathway is normally initiated ing injury is mediated by an increase in Kv2.1 potassium channels in by the oxidative liberation of zinc from intracellular metal-binding the plasma membrane. This phenomenon relies on Kv2.1 binding to proteins (14), leading to the sequential phosphorylation of syntaxin 1A via 9 amino acids within the channel intrinsically disor- Kv2.1 residues Y124 and S800 by Src and p38 kinases, respectively dered C terminus. Preventing this interaction with a cell and blood- (15–17).
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