Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression

Abstract The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. However, the precise role of genetic variants, disrupting the molecular interactions is less understood. All cancer-associated missense variants of ROBO1/4 and SLIT2 from COSMIC were...

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Main Authors: Debmalya Sengupta, Gairika Bhattacharya, Sayak Ganguli, Mainak Sengupta
Format: Article
Language:English
Published: Nature Portfolio 2020-12-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-020-78882-2
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author Debmalya Sengupta
Gairika Bhattacharya
Sayak Ganguli
Mainak Sengupta
author_facet Debmalya Sengupta
Gairika Bhattacharya
Sayak Ganguli
Mainak Sengupta
author_sort Debmalya Sengupta
collection DOAJ
description Abstract The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. However, the precise role of genetic variants, disrupting the molecular interactions is less understood. All cancer-associated missense variants of ROBO1/4 and SLIT2 from COSMIC were screened for their pathogenicity. Homology modelling was done in Modeller 9.17, followed by molecular simulation in GROMACS. Rigid docking was performed for the cognate partners in PatchDock with refinement in HADDOCK server. Post-docking alterations in conformational, stoichiometric, as well as structural parameters, were assessed. The disruptive variants were ranked using a weighted scoring scheme. In silico prioritisation of 825 variants revealed 379 to be potentially pathogenic out of which, about 12% of the variants, i.e. ROBO1 (14), ROBO4 (8), and SLIT2 (23) altered the cognate docking. Six variants of ROBO1 and 5 variants of ROBO4 were identified as "high disruptors" of interactions with SLIT2 wild type. Likewise, 17 and 13 variants of SLIT2 were found to be "high disruptors" of its interaction with ROBO1 and ROBO4, respectively. Our study is the first report on the impact of cancer-associated missense variants on ROBO1/4 and SLIT2 interactions that might be the drivers of lung cancer progression.
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spelling doaj.art-e2cb952c46454be0b8da35efad9f8d182022-12-21T20:35:32ZengNature PortfolioScientific Reports2045-23222020-12-0110111810.1038/s41598-020-78882-2Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progressionDebmalya Sengupta0Gairika Bhattacharya1Sayak Ganguli2Mainak Sengupta3Department of Genetics, University of Calcutta, University College of Science (UCSTA)Department of Genetics, University of Calcutta, University College of Science (UCSTA)Department of Biotechnology, St. Xavier’s College (Autonomous)Department of Genetics, University of Calcutta, University College of Science (UCSTA)Abstract The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. However, the precise role of genetic variants, disrupting the molecular interactions is less understood. All cancer-associated missense variants of ROBO1/4 and SLIT2 from COSMIC were screened for their pathogenicity. Homology modelling was done in Modeller 9.17, followed by molecular simulation in GROMACS. Rigid docking was performed for the cognate partners in PatchDock with refinement in HADDOCK server. Post-docking alterations in conformational, stoichiometric, as well as structural parameters, were assessed. The disruptive variants were ranked using a weighted scoring scheme. In silico prioritisation of 825 variants revealed 379 to be potentially pathogenic out of which, about 12% of the variants, i.e. ROBO1 (14), ROBO4 (8), and SLIT2 (23) altered the cognate docking. Six variants of ROBO1 and 5 variants of ROBO4 were identified as "high disruptors" of interactions with SLIT2 wild type. Likewise, 17 and 13 variants of SLIT2 were found to be "high disruptors" of its interaction with ROBO1 and ROBO4, respectively. Our study is the first report on the impact of cancer-associated missense variants on ROBO1/4 and SLIT2 interactions that might be the drivers of lung cancer progression.https://doi.org/10.1038/s41598-020-78882-2
spellingShingle Debmalya Sengupta
Gairika Bhattacharya
Sayak Ganguli
Mainak Sengupta
Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
Scientific Reports
title Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
title_full Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
title_fullStr Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
title_full_unstemmed Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
title_short Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression
title_sort structural insights and evaluation of the potential impact of missense variants on the interactions of slit2 with robo1 4 in cancer progression
url https://doi.org/10.1038/s41598-020-78882-2
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