Protein Tunnels: The Case of Urease Accessory Proteins

Transition metals are both essential micronutrients and limited in environmental availability. The Ni­(II)-dependent urease protein, the most efficient enzyme known to date, is a paradigm for studying the strategies that cells use to handle an essential, yet toxic, metal ion. Urease is a virulence f...

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Published in:Journal of chemical theory and computation 2017-05, Vol.13 (5), p.2322-2331
Main Authors: Musiani, Francesco, Gioia, Dario, Masetti, Matteo, Falchi, Federico, Cavalli, Andrea, Recanatini, Maurizio, Ciurli, Stefano
Format: Article
Language:English
Subjects:
Activation
Bacterial Proteins - chemistry
Carrier Proteins - chemistry
Catalytic Domain
Crystal structure
Helicobacter Infections - microbiology
Helicobacter pylori - chemistry
Humans
Ions - chemistry
Molecular chains
Molecular dynamics
Molecular Dynamics Simulation
Nickel - chemistry
Pathogens
Protein Conformation
Proteins
Transition metals
Tunnels
Urease - chemistry
Virulence
Water - chemistry
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Summary:Transition metals are both essential micronutrients and limited in environmental availability. The Ni­(II)-dependent urease protein, the most efficient enzyme known to date, is a paradigm for studying the strategies that cells use to handle an essential, yet toxic, metal ion. Urease is a virulence factor of several human pathogens, in addition to decreasing the efficiency of soil organic nitrogen fertilization. Ni­(II) insertion in the urease active site is performed through the action of three essential accessory proteins: UreD, UreF, and UreG. The crystal structure of the UreD-UreF-UreG complex from the human pathogen Helicobacter pylori (HpUreDFG) revealed the presence of tunnels that cross the entire length of both UreF and UreD, potentially able to deliver Ni­(II) ions from UreG to apo-urease. Atomistic molecular dynamics simulations performed on the HpUreDFG complex in explicit solvent and at physiological ionic conditions demonstrate the stability of these protein tunnels in solution and provide insights on the trafficking of water molecules inside the tunnels. The presence of different alternative routes across the identified tunnels for Ni­(II) ions, water molecules, and carbonate ions, all involved in urease activation, is highlighted here, and their potential role in the urease activation mechanism is discussed.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.7b00042