title: Large-scale conformational flexibility determines the properties of AAA+ TIP49 ATPases.
abstract: The TIP49a and TIP49b proteins belong to the family of AAA+ ATPases and play essential roles in vital processes such as transcription, DNA repair, snoRNP biogenesis, and chromatin remodeling. We report the crystal structure of a TIP49b hexamer and the comparative analysis of large-scale conformational flexibility of TIP49a, TIP49b, and TIP49a/TIP49b complexes using molecular modeling and molecular dynamics simulations in a water environment. Our results establish key principles of domain mobility that affect protein conformation and biochemical properties, including a mechanistic basis for the downregulation of ATPase activity upon protein hexamerization. These approaches, applied to the lik-TIP49b mutant reported to possess enhanced DNA-independent ATPase activity, help explain how a three-amino acid insertion remotely affects the structure and conformational dynamics of the ATP binding and hydrolysis pocket while uncoupling ATP hydrolysis from DNA binding. This might be similar to the effects of conformations adopted by TIP49 heterohexamers.
authors: Department of Biophysics, Saint Petersburg State Polytechnical University, Saint Petersburg 197376, Russia.
authors: Michael
authors: M
authors: Petukhov
authors: Adilia
authors: A
authors: Dagkessamanskaja
authors: Martin
authors: M
authors: Bommer
authors: Tracey
authors: T
authors: Barrett
authors: Irina
authors: I
authors: Tsaneva
authors: Alexander
authors: A
authors: Yakimov
authors: Richard
authors: R
authors: Quéval
authors: Alexey
authors: A
authors: Shvetsov
authors: Mikhail
authors: M
authors: Khodorkovskiy
authors: Emmanuel
authors: E
authors: Käs
authors: Mikhail
authors: M
authors: Grigoriev
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000255:Adenosine Triphosphate / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004265:DNA Helicases / Q000737:chemistry*; D004795:Enzyme Stability; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D002352:Carrier Proteins; D000255:Adenosine Triphosphate; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human