Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia
Mutations in Valosin-containing protein (VCP) have been implicated in the pathology linked to inclusion body myopathy, paget disease of bone and frontotemporal dementia (IBMPFD). VCP is an essential component of AAA-ATPase superfamily involved in various cellular functions. Advanced In-silico analys...
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doaj-e4d118f5db2d476d9f350d8d3d6821352021-04-04T04:18:25ZengElsevierSaudi Journal of Biological Sciences1319-562X2021-04-0128421282138Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal DementiaRui Wu0Zhijie Wei1Li Zhang2Corresponding author: Department of Neurology, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan District, Zunyi, Guizhou 563000, China.; Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, ChinaDepartment of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, ChinaDepartment of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, ChinaMutations in Valosin-containing protein (VCP) have been implicated in the pathology linked to inclusion body myopathy, paget disease of bone and frontotemporal dementia (IBMPFD). VCP is an essential component of AAA-ATPase superfamily involved in various cellular functions. Advanced In-silico analysis was performed using prediction based servers to determine the most deleterious mutation. Molecular dynamics simulation was used to study the protein dynamics at atomic level. Molecular docking was used to study the effect of mutation on ATP/ADP transition in the kinase domain. This ATPase of 806 amino acids has four domains: N-terminal domain, C-terminal domain and two ATPase domains D1 and D2 and each of these domains have a distinct role in its functioning. The mutations in VCP protein are distributed among regions known as hotspots, one such hotspot is codon 155. Three missense mutations reported in this hotspot are R155C, R155H and R155P. Potentiality of the deleteriousness calculated using server based prediction models reveal R155C mutation to be the most deleterious. The atomic insight into the effect of mutation by molecular dynamics simulation revealed major conformational changes in R155C variants ATP binding site in D1 domain. The nucleotide-binding mode at the catalytic pocket of VCP and its three variants at codon 155 showed change in the structure, which affects the ATP–ADP transition kinetics in all the three variants.http://www.sciencedirect.com/science/article/pii/S1319562X21001212Valosin-containing proteinMyopathyPaget diseaseDementiaMolecular docking |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rui Wu Zhijie Wei Li Zhang |
spellingShingle |
Rui Wu Zhijie Wei Li Zhang Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia Saudi Journal of Biological Sciences Valosin-containing protein Myopathy Paget disease Dementia Molecular docking |
author_facet |
Rui Wu Zhijie Wei Li Zhang |
author_sort |
Rui Wu |
title |
Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia |
title_short |
Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia |
title_full |
Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia |
title_fullStr |
Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia |
title_full_unstemmed |
Structural insight into mutations at 155 position of valosin containing protein (VCP) linked to inclusion body myopathy with Paget disease of bone and frontotemporal Dementia |
title_sort |
structural insight into mutations at 155 position of valosin containing protein (vcp) linked to inclusion body myopathy with paget disease of bone and frontotemporal dementia |
publisher |
Elsevier |
series |
Saudi Journal of Biological Sciences |
issn |
1319-562X |
publishDate |
2021-04-01 |
description |
Mutations in Valosin-containing protein (VCP) have been implicated in the pathology linked to inclusion body myopathy, paget disease of bone and frontotemporal dementia (IBMPFD). VCP is an essential component of AAA-ATPase superfamily involved in various cellular functions. Advanced In-silico analysis was performed using prediction based servers to determine the most deleterious mutation. Molecular dynamics simulation was used to study the protein dynamics at atomic level. Molecular docking was used to study the effect of mutation on ATP/ADP transition in the kinase domain. This ATPase of 806 amino acids has four domains: N-terminal domain, C-terminal domain and two ATPase domains D1 and D2 and each of these domains have a distinct role in its functioning. The mutations in VCP protein are distributed among regions known as hotspots, one such hotspot is codon 155. Three missense mutations reported in this hotspot are R155C, R155H and R155P. Potentiality of the deleteriousness calculated using server based prediction models reveal R155C mutation to be the most deleterious. The atomic insight into the effect of mutation by molecular dynamics simulation revealed major conformational changes in R155C variants ATP binding site in D1 domain. The nucleotide-binding mode at the catalytic pocket of VCP and its three variants at codon 155 showed change in the structure, which affects the ATP–ADP transition kinetics in all the three variants. |
topic |
Valosin-containing protein Myopathy Paget disease Dementia Molecular docking |
url |
http://www.sciencedirect.com/science/article/pii/S1319562X21001212 |
work_keys_str_mv |
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