期刊
BIOCHEMICAL JOURNAL
卷 454, 期 -, 页码 459-466出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20121907
关键词
microtubule-associated protein light chain 3 beta (LC3); NMR spectroscopy; optineurin; protein-protein interaction; selective autophagy; X-ray crystallography
资金
- Center for Biomolecular Magnetic Resonance (BMRZ)
- Cluster of Excellence Frankfurt Macromolecular Complexes (CEF)
- Volkswagen Foundation
- Marie Curie ENDOCYTE training network
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 TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor kappa B activator]-binding kinase 1}. In the present study we describe the NMR and crystal structures of the autophagy modifier LC3B (microtubule-associated protein light chain 3 beta) 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 Arg(11) and Lys(51) in LC3B. Further mutational analysis suggests that the replacement of the canonical tryptophan residue side chain of autophagy receptors with the smaller phenylalanine side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serine residues directly N-terminally located to the phenylalanine 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.
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