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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Autores principales:	Debmalya Sengupta, Gairika Bhattacharya, Sayak Ganguli, Mainak Sengupta
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e2cb952c46454be0b8da35efad9f8d18
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spelling	oai:doaj.org-article:e2cb952c46454be0b8da35efad9f8d182021-12-02T12:42:18ZStructural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression10.1038/s41598-020-78882-22045-2322https://doaj.org/article/e2cb952c46454be0b8da35efad9f8d182020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78882-2https://doaj.org/toc/2045-2322Abstract 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.Debmalya SenguptaGairika BhattacharyaSayak GanguliMainak SenguptaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-18 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Debmalya Sengupta Gairika Bhattacharya Sayak Ganguli Mainak Sengupta
author_facet	Debmalya Sengupta Gairika Bhattacharya Sayak Ganguli Mainak Sengupta
author_sort	Debmalya Sengupta
title	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_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_sort	structural insights and evaluation of the potential impact of missense variants on the interactions of slit2 with robo1/4 in cancer progression
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/e2cb952c46454be0b8da35efad9f8d18
work_keys_str_mv	AT debmalyasengupta structuralinsightsandevaluationofthepotentialimpactofmissensevariantsontheinteractionsofslit2withrobo14incancerprogression AT gairikabhattacharya structuralinsightsandevaluationofthepotentialimpactofmissensevariantsontheinteractionsofslit2withrobo14incancerprogression AT sayakganguli structuralinsightsandevaluationofthepotentialimpactofmissensevariantsontheinteractionsofslit2withrobo14incancerprogression AT mainaksengupta structuralinsightsandevaluationofthepotentialimpactofmissensevariantsontheinteractionsofslit2withrobo14incancerprogression
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Structural insights and evaluation of the potential impact of missense variants on the interactions of SLIT2 with ROBO1/4 in cancer progression

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