Original Research ARTICLE
Structural analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 interactions for its implications in recovER-phagy in Plasmodium falciparum
- 1Indian Institute of Petroleum and Energy (IIPE), India
- 2Jawaharlal Nehru Centre for Advanced Scientific Research, India
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 (PfAtg8) 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 PfSec62 by carrying out peptide-protein docking simulations and comparing the interactions of these AIMs with PfAtg8, 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 (ΔGdissociation) using Jarzynski’s equality were also computed for the AIM/LIR motif complexes with PfAtg8/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.
Keywords: Autophagy, Plasmodium falciparium, recovER-phagy, PfSec62-PfAtg8 interactions, AIM/LIR motifs
Received: 05 Jun 2019;
Accepted: 11 Sep 2019.
Copyright: © 2019 Mamidi, Ray and Surolia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Namita Surolia, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India, email@example.com