Methionine as a redox switch regulating biological activities of cofilin

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	FDA/CBER	MOLBIO-21

Authors

• H Uehara
• E Shacter
• S Luo

Abstract

Cofilin regulates reorganization of actin filaments (F-actin ). It accelerates F-actin depolymerization by promoting dissociation of monomeric globular-actin (G-actin) in a complex with cofilin, which requires a functional G-actin-binding site on cofilin. Taurine chloramine (TnCl), a physiological oxidant generated during inflammation, oxidizes Cys and Met on cofilin, but the effect of oxidation on its biological activity has not been studied. We found that TnCl inhibits recombinant human cofilin-1 to bind and depolymerize F-actin. DTT does not reactivate TnCl-treated cofilin. A double Cys to Ala mutation shows similar biological activities as the wild type, but does not prevent the TnCl-induced inactivation. Incubate oxidized cofilin with methionine sulfoxide reductases leads to reduction of methionine sulfoxide back to Met, resulting in reactivation. Interestingly, the oxidized mutant contains one major oxidation product with +16 Da mass shift, consistent with oxidation of one specific Met. This residue was identified as Met-115, located in the G-actin-binding pocket, implying that oxidation of Met-115 disrupts the G-actin-binding site of cofilin and causes inactivation. Phosphorylation is well-known to regulate cofilin activity. It is also inhibited by Met oxidation and restored by methionine sulfoxide reductases. The findings identify Met-115 as a redox switch on cofilin which regulates its biological activities.

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