Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum
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 reco...
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fbioe.2019.00240/full |
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| author | Ashalatha Sreshty Mamidi Ashalatha Sreshty Mamidi Ananya Ray Namita Surolia |
| author_facet | Ashalatha Sreshty Mamidi Ashalatha Sreshty Mamidi Ananya Ray Namita Surolia |
| author_sort | Ashalatha Sreshty Mamidi |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-12-23T19:54:08Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-81ead59aae1b4751b6c28c2211b532f22022-12-21T17:33:17ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852019-09-01710.3389/fbioe.2019.00240476880Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparumAshalatha Sreshty Mamidi0Ashalatha Sreshty Mamidi1Ananya Ray2Namita Surolia3Molecular Biophysics Unit, Indian Institute of Science, Bangalore, IndiaDivision of Biological Sciences, Indian Institute of Petroleum and Energy, Visakhapatnam, IndiaMolecular Biology and Genetics Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaMolecular Biology and Genetics Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaAutophagy 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.https://www.frontiersin.org/article/10.3389/fbioe.2019.00240/fullautophagyrecovER-phagyPfSec62-PfAtg8 interactionsAIM/LIR motifsPlasmodium falciparum |
| spellingShingle | Ashalatha Sreshty Mamidi Ashalatha Sreshty Mamidi Ananya Ray Namita Surolia 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 autophagy recovER-phagy PfSec62-PfAtg8 interactions AIM/LIR motifs Plasmodium falciparum |
| title | Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum |
| title_full | Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum |
| title_fullStr | Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum |
| title_full_unstemmed | Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum |
| title_short | Structural Analysis of PfSec62-Autophagy Interacting Motifs (AIM) and PfAtg8 Interactions for Its Implications in RecovER-phagy in Plasmodium falciparum |
| title_sort | structural analysis of pfsec62 autophagy interacting motifs aim and pfatg8 interactions for its implications in recover phagy in plasmodium falciparum |
| topic | autophagy recovER-phagy PfSec62-PfAtg8 interactions AIM/LIR motifs Plasmodium falciparum |
| url | https://www.frontiersin.org/article/10.3389/fbioe.2019.00240/full |
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