Inositol Hexaphosphate as an Inhibitor and Potential Regulator of p47 ^phox Membrane Anchoring.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE

Original Publication: Washington, American Chemical Society.

Phytic Acid*/metabolism ; Phytic Acid*/chemistry ; NADPH Oxidases*/metabolism ; NADPH Oxidases*/antagonists & inhibitors; Humans ; Cell Membrane/metabolism ; NADPH Oxidase 2/metabolism ; Phosphatidylinositol Phosphates/metabolism

As a key component for NADPH oxidase 2 (NOX2) activation, the peripheral membrane protein p47 ^phox translocates a cytosolic activating complex to the membrane through its PX domain. This study elucidates a potential regulatory mechanism of p47 ^phox recruitment and NOX2 activation by inositol hexaphosphate (IP6). Through NMR, fluorescence polarization, and FRET experimental results, IP6 is shown to be capable of breaking the lipid binding and membrane anchoring events of p47 ^phox -PX with low micromolar potency. Other phosphorylated inositol species such as IP5(1,3,4,5,6), IP4(1,3,4,5), and IP3(1,3,4) show weaker binding and no ability to inhibit lipid interactions in physiological concentration ranges. The low micromolar potency of IP6 inhibition of the p47 ^phox membrane anchoring suggests that physiologically relevant concentrations of IP6 serve as regulators, as seen in other membrane anchoring domains. The PX domain of p47 ^phox is known to be promiscuous to a variety of phosphatidylinositol phosphate (PIP) lipids, and this regulation may help target the domain only to the membranes most highly enriched with the highest affinity PIPs, such as the phagosomal membrane, while preventing aberrant binding to other membranes with high and heterogeneous PIP content, such as the plasma membrane. This study provides insight into a potential novel regulatory mechanism behind NOX2 activation and reveals a role for small-molecule regulation in this important NOX2 activator.

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R35 GM147221 United States GM NIGMS NIH HHS

7IGF0S7R8I (Phytic Acid)
EC 1.6.3.- (NADPH Oxidases)
EC 1.6.3.1 (neutrophil cytosolic factor 1)
EC 1.6.3.- (NADPH Oxidase 2)
0 (Phosphatidylinositol Phosphates)

Date Created: 20240426 Date Completed: 20240507 Latest Revision: 20241015

20241015

PMC11080064

10.1021/acs.biochem.4c00117

38669178