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

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• 作者：Arina Afanasyeva¹ ; ⁵ ; ⁸ ; Angela Hirtreiter² ; ⁸ ; Anne Schreiber² ; ⁸ ; ⁹ ; Dina Grohmann³ ; Georgii Pobegalov¹ ; Adam R. McKay⁴ ; Irina Tsaneva² ; Michael Petukhov¹ ; ⁵ ; Emmanuel K&auml ; s⁶ ; ⁷ ; ^{kas@ibcg.biotoul.fr" class="auth_mail} ; Mikhail Grigoriev⁶ ; ⁷ ; ^{grigor@biotoul.fr" class="auth_mail} ; Finn Werner²
• 刊名：Structure
• 出版年：8 April, 2014
• 年：2014
• 卷：22
• 期：4
• 页码：549-559
• 全文大小：1699 K

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lass="h3">Summary

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