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Phosphorylation of the LIR domain of SCOC modulates ATG8 binding affinity and specificity

DOI: 10.1016/j.jmb.2021.166987 DOI Help

Authors: Martina Wirth (The Francis Crick Institute; Leiden University Medical Center) , Stephane Mouilleron (The Francis Crick Institute) , Wenxin Zhang (The Francis Crick Institute (Midland Road)) , Eva Sjøttem (University of Tromsø - The Arctic University of Norway) , Yakubu Princely Abudu (University of Tromsø - The Arctic University of Norway) , Ashish Jain (University of Tromsø - The Arctic University of Norway; The Norwegian Radium Hospital) , Hallvard Lauritz Olsvik (University of Tromsø - The Arctic University of Norway) , Jack-Ansgar Bruun (University of Tromsø - The Arctic University of Norway) , Minoo Razi (The Francis Crick Institute) , Harold B. J. Jefferies (The Francis Crick Institute) , Rebecca Lee (The Francis Crick Institute) , Dhira Joshi (The Francis Crick Institute) , Nicola O'Reilly (The Francis Crick Institute) , Terje Johansen (University of Tromsø - The Arctic University of Norway) , Sharon A. Tooze (The Francis Crick Institute; The Norwegian Radium Hospital)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 433

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 9826

Open Access Open Access

Abstract: Autophagy is a highly conserved degradative pathway, essential for cellular homeostasis and implicated in diseases including cancer and neurodegeneration. Autophagy-related 8 (ATG8) proteins play a central role in autophagosome formation and selective delivery of cytoplasmic cargo to lysosomes by recruiting autophagy adaptors and receptors. The LC3-interacting region (LIR) docking site (LDS) of ATG8 proteins binds to LIR motifs present in autophagy adaptors and receptors. LIR-ATG8 interactions can be highly selective for specific mammalian ATG8 family members (LC3A-C, GABARAP, and GABARAPL1-2) and how this specificity is generated and regulated is incompletely understood. We have identified a LIR motif in the Golgi protein SCOC (short coiled-coil protein) exhibiting strong binding to GABARAP, GABARAPL1, LC3A and LC3C. The residues within and surrounding the core LIR motif of the SCOC LIR domain were phosphorylated by autophagy-related kinases (ULK1-3, TBK1) increasing specifically LC3 family binding. More distant flanking residues also contributed to ATG8 binding. Loss of these residues was compensated by phosphorylation of serine residues immediately adjacent to the core LIR motif, indicating that the interactions of the flanking LIR regions with the LDS are important and highly dynamic. Our comprehensive structural, biophysical and biochemical analyses support and provide novel mechanistic insights into how phosphorylation of LIR domain residues regulates the affinity and binding specificity of ATG8 proteins towards autophagy adaptors and receptors.

Journal Keywords: autophagy; LIR motif; phosphorylation; bio-layer interferometry; crystal structure

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
1-s2.0-S0022283621001881-main.pdf

Discipline Tags:

Biochemistry Chemistry Health & Wellbeing Life Sciences & Biotech Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)