Structure of V-ATPase from the mammalian brain

  • Science. 2020 Mar 13;367(6483):1240-1246. doi: 10.1126/science.aaz2924.
Yazan M Abbas  1 ,  Di Wu  2 ,  Stephanie A Bueler  1 ,  Carol V Robinson  2 ,  John L Rubinstein  3  4  5
Affiliations
  • 1. Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
  • 2. Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford OX1 3QZ, UK.
  • 3. Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada. [email protected].
  • 4. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 5. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
PMID: 32165585 DOI: 10.1126/science.aaz2924
Abstract

In neurons, the loading of neurotransmitters into synaptic vesicles uses energy from proton-pumping vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases). These membrane protein complexes possess numerous subunit isoforms, which complicates their analysis. We isolated homogeneous rat brain V-ATPase through its interaction with SidK, a Legionella pneumophila effector protein. Cryo-electron microscopy allowed the construction of an atomic model, defining the enzyme's ATP:proton ratio as 3:10 and revealing a homolog of yeast subunit f in the membrane region, which we tentatively identify as RNAseK. The c ring encloses the transmembrane anchors for cleaved ATP6AP1/Ac45 and ATP6AP2/PRR, the latter of which is the (pro)Renin receptor that, in Other contexts, is involved in both Wnt signaling and the renin-angiotensin system that regulates blood pressure. This structure shows how ATP6AP1/Ac45 and ATP6AP2/PRR enable assembly of the enzyme's catalytic and membrane regions.