2lue

Publication Abstract from PubMed

Selective autophagy is mediated by the interaction of autophagy modifiers and autophagy receptors that also bind to ubiquitinated cargo. Optineurin is an autophagy receptor that plays a role in the clearance of cytosolic Salmonella. The interaction between receptors and modifiers is often relatively weak, with typical values for the dissociation constant in the low micromolar range. The interaction of optineurin with autophagy modifiers is even weaker but can be significantly enhanced through phosphorylation by the TANK binding kinase 1. Here we present the NMR and crystal structures of the autophagy modifier LC3B in complex with the LC3 interaction region of optineurin either phosphorylated or bearing phospho-mimicking mutations. The structures show that the negative charge induced by phosphorylation is recognized by the side-chains of Arg11 and Lys51 in LC3B. Further mutational analysis suggests that the replacement of the canonical Trp side chain of autophagy receptors with the smaller Phe side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serines directly N-terminally located to the Phe residue, the affinity is increased to the level normally seen for receptor - modifier interactions. Phosphorylation, therefore, acts as a switch for optineurin-based selective autophagy.

Structural basis for phosphorylation-triggered autophagic clearance of Salmonella.,Rogov VV, Suzuki H, Fiskin E, Wild P, Kniss A, Rozenknop A, Kato R, Kawasaki M, McEwan DG, Lohr F, Guntert P, Dikic I, Wakatsuki S, Dotsch V Biochem J. 2013 Jun 28. PMID:23805866^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.