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Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity.

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.

SUBMITTER: Wirth M

PROVIDER: S-EPMC8202330 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity.

Wirth Martina M Mouilleron Stephane S Zhang Wenxin W Sjøttem Eva E Princely Abudu Yakubu Y Jain Ashish A Lauritz Olsvik Hallvard H Bruun Jack-Ansgar JA Razi Minoo M Jefferies Harold B J HBJ Lee Rebecca R Joshi Dhira D O'Reilly Nicola N Johansen Terje T Tooze Sharon A SA

Journal of molecular biology 20210424 13

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 c ...[more]

PMID: 33845085

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Project description:The gp120 surface subunit of HIV-1 envelope lycoprotein (Env) is the key component for the viral entry process through interaction with the CD4 binding site (CD4bs) of the primary receptor CD4. The point mutant was introduced into SD1, a CD4 D1 variant, to enhance the interaction with HIV-1 gp120.The three-dimensional structures of gp120 and SD1 were determined using homology modeling based on the results previously determined by X-ray crystallography. The binding models were carried out via protein-protein docking tools. The 5 best docking solutions were retained according to the docking scores and were used for structural assessment. Our results demonstrated the consistency between the 3D models of gp120 and SD1 predicted by molecular docking calculations and the co-crystallized data available. We first discovered that most residues in SD1 that interacted with gp120 were located within the region 6-94 of the first N-terminal D1 domain of CD4. SD1 bound to gp120 stably at which 15 residues formed 20 hydrogen bonds with 16 residues of gp120. Five pairs of electrostatic interactions between positively and negatively charged side chains of amino acids were identified in the SD1-gp120 interface, which showed an increased number of electrostatic interactions with gp120. The mutant in the D1 domain of human CD4 receptor could strengthen binding affinity with HIV-1 gp120 and might improve the interaction pattern of the neighboring residues. The sequence analysis of gp120 suggested that Asp186, Asn189, Arg191, Glu293, Phe318 and Tyr319 were located in the variable regions of gp120, which may be HIV-1 AE strain-specific amino acid residues. Together, the results presented in this study contributed to a better understanding of the changes in the interaction between the gp120 protein and the human host CD4 receptor associated with point mutation in the D1 domain. The stabilized derivative of human CD4 D1 should serve as a promising target for therapeutics development in HIV-1 vaccine and viral entry inhibitor and may warrant further investigation.

Dataset Information

Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity.

Publications

Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity.

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