Lytic Water Dynamics Reveal Evolutionarily Conserved Mechanisms of ATP Hydrolysis by TIP49 AAA+ ATPases

• DOI: 10.1016/j.str.2014.02.002
• Publication Date: 2014-03-08T00:30:54Z
• Authors: Arina Afanasyeva; Angela Hirtreiter; Anne Schreiber; Dina Grohmann; Georgii Pobegalov; Adam R. McKay; Irina Tsaneva; Michael Petukhov; Emmanuel Käs; Mikhail Grigoriev; Finn Werner
• Keywords: Lytic cycle; AAA proteins; Walker motifs; Crosstalk; Conserved sequence

Eukaryotic TIP49a (Pontin) and TIP49b (Reptin) AAA+ ATPases play essential roles in key cellular processes. How their weak ATPase activity contributes to important functions remains largely unknown difficult analyze because of the divergent properties proteins homo- hetero-oligomeric assemblies. To circumvent these complexities, we have analyzed single ancient TIP49 ortholog found archaeon Methanopyrus kandleri (mkTIP49). All-atom homology modeling molecular dynamics simulations validated by biochemical assays reveal highly conserved organizational principles identify residues for ATP hydrolysis. An unanticipated crosstalk between Walker B Sensor I motifs impacts water molecules highlights a critical role trans-acting aspartates lytic activation step that is associative mechanism