Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics
Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies...
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doaj-882490aba3f94907865b2b1f3d2eb6e22021-08-02T04:39:38ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011941564164Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamicsShuheng Huang0Hu Mei1Laichun Lu2Zuyin Kuang3Yu Heng4Lei Xu5Xiaoqi Liang6Minyao Qiu7Xianchao Pan8Key Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, China; Corresponding authors at: Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing 400044, China (H. Mei) and (L. Lu).Key Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, China; Corresponding authors at: Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing 400044, China (H. Mei) and (L. Lu).Key Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaKey Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, ChinaDepartment of Medicinal Chemistry, College of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Corresponding authors at: Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing 400044, China (H. Mei) and (L. Lu).Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60′s, 90′s and 130′s helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60′s and 130′s extended helices. The H-bond interactions between L1, 130′s helix and 90′s helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors.http://www.sciencedirect.com/science/article/pii/S200103702100307XCaspase-6Conformational transitionPerturbation-response scanningTargeted molecular dynamicsH-bond interactions |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shuheng Huang Hu Mei Laichun Lu Zuyin Kuang Yu Heng Lei Xu Xiaoqi Liang Minyao Qiu Xianchao Pan |
spellingShingle |
Shuheng Huang Hu Mei Laichun Lu Zuyin Kuang Yu Heng Lei Xu Xiaoqi Liang Minyao Qiu Xianchao Pan Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics Computational and Structural Biotechnology Journal Caspase-6 Conformational transition Perturbation-response scanning Targeted molecular dynamics H-bond interactions |
author_facet |
Shuheng Huang Hu Mei Laichun Lu Zuyin Kuang Yu Heng Lei Xu Xiaoqi Liang Minyao Qiu Xianchao Pan |
author_sort |
Shuheng Huang |
title |
Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
title_short |
Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
title_full |
Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
title_fullStr |
Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
title_full_unstemmed |
Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
title_sort |
conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics |
publisher |
Elsevier |
series |
Computational and Structural Biotechnology Journal |
issn |
2001-0370 |
publishDate |
2021-01-01 |
description |
Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60′s, 90′s and 130′s helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60′s and 130′s extended helices. The H-bond interactions between L1, 130′s helix and 90′s helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors. |
topic |
Caspase-6 Conformational transition Perturbation-response scanning Targeted molecular dynamics H-bond interactions |
url |
http://www.sciencedirect.com/science/article/pii/S200103702100307X |
work_keys_str_mv |
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