Abstract
Author SummaryCatalytic activities of many important enzymes depend upon metal cofactors. Ensuring each enzyme acquires the proper type of metal cofactor is essential to life. One such example is urease, which is a nickel containing metalloenzyme catalyzing the hydrolysis of urea to ammonia. The survival of Helicobacter pylori, a stomach ulcer–causing pathogen, in the human stomach depends on the ammonia released to neutralize gastric acid. In this study, we revealed the detail mechanism of how urease accessory proteins UreF, UreH, and UreG cooperate to couple GTP hydrolysis to deliver nickel to urease. UreF/UreH complex interacts with two molecules of GTPase UreG and assembles a metal binding site located at the interface between two UreG molecules. Nickel can induce GTP-dependent dimerization of UreG. This nickel-carrying UreG dimer together with UreF, UreH, and urease assemble into a protein complex. Upon stimulation of UreG GTPase activity by bicarbonate, UreG hydrolyses GTP and releases nickel into urease. Other nickel-delivering NTPases share similar properties with UreG; therefore, the nickel delivery mechanism described here is likely universally shared among these proteins.
Highlights
More than a quarter of the cellular proteins are metalloproteins [1]
The survival of Helicobacter pylori, a stomach ulcer–causing pathogen, in the human stomach depends on the ammonia released to neutralize gastric acid
We revealed the detail mechanism of how urease accessory proteins UreF, UreH, and UreG cooperate to couple guanosine triphosphate (GTP) hydrolysis to deliver nickel to urease
Summary
More than a quarter of the cellular proteins are metalloproteins [1]. Homeostatic regulation on the incorporation of specific metal ions to these metalloproteins is essential to life. Metal ions that occupy the top of the Irving-Williams series [2], such as nickel, copper, and zinc, form stable complexes with proteins. These metals must be tightly regulated in the cell to be kept out of other proteins that require less competitive metals to function. Urease is a nickel containing metalloenzyme that hydrolyses urea into ammonia. Its activity enables Helicobacter pylori to survive under strongly acidic conditions of the human stomach by neutralizing gastric acid with the ammonia released [4]. Maturation of urease, a process that involves the delivery of two nickel ions into the carbamylated active site of the apo-enzyme, offers a paradigm to study metallochaperone-driven incorporation of metal into metalloenzyme
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