The dynamic interplay of PIP2 and ATP in the regulation of the KATP channel Tanadet Pipatpolkai University of Warwick Samuel Usher University of Oxford Natascia Vedovato University of Oxford Frances Ashcroft University of Oxford Phillip Stansfeld (
[email protected] ) University of Warwick https://orcid.org/0000-0001-8800-7669 Article Keywords: ATP-sensitive potassium channel, molecular dynamics, phosphatidylinositol bisphosphate Posted Date: April 29th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-445411/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License The dynamic interplay of PIP2 and ATP in the regulation of the KATP channel Tanadet Pipatpolkai1,2,3, Samuel G. Usher1,3,+, Natascia Vedovato1,+, Frances M Ashcroft1,*, Phillip J. Stansfeld4,* 1Department of Physiology Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK. 2Department of Biochemistry, South Parks Road, Oxford, OX1 3QU, UK. 3OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, UK. 4School of Life Sciences & Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK. *corresponding authors +,*,These authors contributed equally to the work 1 Abstract ATP-sensitive potassium (KATP) channels couple the intracellular ATP concentration to insulin secretion. KATP channel activity is inhibited by ATP binding to the Kir6.2 tetramer and activated by phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we use molecular dynamics (MD) simulation, electrophysiology and fluorescence spectroscopy to show that ATP and PIP2 occupy different binding pockets that share a single amino acid residue, K39. When both ligands are present, K39 shows a greater preference to co-ordinate with PIP2 than ATP.