Autophagy is a degradative pathway associated with many pathological and physiological processes crucial for cell survival. During ER stress, while selective autophagy occurs via ER-phagy, the re-establishment of physiologic ER homeostasis upon resolution of a transient ER stress is mediated by recovER-phagy. Recent studies demonstrated that recovER-phagy is governed via association of Sec62 as an ER-resident autophagy receptor through its autophagy interacting motifs (AIM)/LC3-interacting region (LIR) toAtg8/LC3. Atg8 is an autophagy protein, which is central to autophagosome formation and maturation. Plasmodium falciparum Atg8 (Pf Atg8) has both autophagic and non-autophagic functions critical for parasite survival. Since Plasmodium also has Sec62 in the ER membrane and is prone to ER stress due to drastic transformation during their complex intraerythrocytic cycle; hence, we initiated the studies to check whether recovER-phagy occurs in the parasite. To achieve this, a comprehensive study based on the computational approaches was carried out. This study embarks upon identification of AIM sequences in Pf Sec62 by carrying out peptide-protein docking simulations and comparing the interactions of these AIMs with Pf Atg8, based on the molecular dynamic simulations. Detailed analysis is based on electrostatic surface complementarity, peptide-protein interaction strength, mapping of non-covalent bond interactions and rupture force calculated from steered MD simulations. Potential mean forces and unbinding free energies (∆Gdissociation ) using Jarzynski’s equality were also computed for the AIM/LIR motif complexes with Pf Atg8/HsLC3 autophagy proteins to understand their dissociation free energy profiles and thereby their binding affinities and stability of the peptide-protein complexes. Through this study, we predict Sec62 mediated recovER-phagy in Plasmodium falciparum, which might open new avenues to explore novel drug targets for antimalarial drug discovery.
CITATION STYLE
Mamidi, A. S., Ray, A., & Surolia, N. (2019). Structural analysis of pfsec62-autophagy interacting motifs (AIM) and pfAtg8 interactions for its implications in recover-phagy in plasmodium falciparum. Frontiers in Bioengineering and Biotechnology, 7(SEP). https://doi.org/10.3389/fbioe.2019.00240
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