Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50

Abstract BRCA1 associated ring domain protein 1(BARD1) is a tumor suppressor protein having a wide role in cellular processes like cell-cycle checkpoint, DNA damage repair and maintenance of genomic integrity. Germ-line mutation Gln 564 His discovered in linker region of BARD1 leads to loss of bindi...

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Autores principales:	Rajan Kumar Choudhary, Mohd Quadir Siddiqui, Pankaj S. Thapa, Nikhil Gadewal, Senthil Kumar Nachimuthu, Ashok K. Varma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bf40bf00aad3482ab15109c7ad448f44
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spelling	oai:doaj.org-article:bf40bf00aad3482ab15109c7ad448f442021-12-02T15:05:39ZStructural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF5010.1038/s41598-017-03816-42045-2322https://doaj.org/article/bf40bf00aad3482ab15109c7ad448f442017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03816-4https://doaj.org/toc/2045-2322Abstract BRCA1 associated ring domain protein 1(BARD1) is a tumor suppressor protein having a wide role in cellular processes like cell-cycle checkpoint, DNA damage repair and maintenance of genomic integrity. Germ-line mutation Gln 564 His discovered in linker region of BARD1 leads to loss of binding to Cleavage stimulating factor (CstF50), which in turn instigates the premature mRNA transcript formation and apoptosis. We have studied the dynamics of ARD domain present in the BARD1 wild-type and mutant protein in association with CstF50 using biophysical, biochemical and molecular dynamics simulations. It has been observed that the ARD domain is relatively more flexible than the BRCT domain of BARD1. Further relative orientations of both the ARD and BRCT domains varies due to the highly flexible nature of the connecting linker region present between the domains. It has been observed that mutant ARD domain is more dynamic in nature compared to wild-type protein. Molecular docking studies between BARD1 Gln 564 His mutant and CstF50 shows the loss of interactions. Furthermore, domain motion of ARD present in BARD1 was stabilized when complexed with CstF50.Rajan Kumar ChoudharyMohd Quadir SiddiquiPankaj S. ThapaNikhil GadewalSenthil Kumar NachimuthuAshok K. VarmaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rajan Kumar Choudhary Mohd Quadir Siddiqui Pankaj S. Thapa Nikhil Gadewal Senthil Kumar Nachimuthu Ashok K. Varma Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
description	Abstract BRCA1 associated ring domain protein 1(BARD1) is a tumor suppressor protein having a wide role in cellular processes like cell-cycle checkpoint, DNA damage repair and maintenance of genomic integrity. Germ-line mutation Gln 564 His discovered in linker region of BARD1 leads to loss of binding to Cleavage stimulating factor (CstF50), which in turn instigates the premature mRNA transcript formation and apoptosis. We have studied the dynamics of ARD domain present in the BARD1 wild-type and mutant protein in association with CstF50 using biophysical, biochemical and molecular dynamics simulations. It has been observed that the ARD domain is relatively more flexible than the BRCT domain of BARD1. Further relative orientations of both the ARD and BRCT domains varies due to the highly flexible nature of the connecting linker region present between the domains. It has been observed that mutant ARD domain is more dynamic in nature compared to wild-type protein. Molecular docking studies between BARD1 Gln 564 His mutant and CstF50 shows the loss of interactions. Furthermore, domain motion of ARD present in BARD1 was stabilized when complexed with CstF50.
format	article
author	Rajan Kumar Choudhary Mohd Quadir Siddiqui Pankaj S. Thapa Nikhil Gadewal Senthil Kumar Nachimuthu Ashok K. Varma
author_facet	Rajan Kumar Choudhary Mohd Quadir Siddiqui Pankaj S. Thapa Nikhil Gadewal Senthil Kumar Nachimuthu Ashok K. Varma
author_sort	Rajan Kumar Choudhary
title	Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
title_short	Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
title_full	Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
title_fullStr	Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
title_full_unstemmed	Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50
title_sort	structural basis to stabilize the domain motion of bard1-ard brct by cstf50
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bf40bf00aad3482ab15109c7ad448f44
work_keys_str_mv	AT rajankumarchoudhary structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50 AT mohdquadirsiddiqui structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50 AT pankajsthapa structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50 AT nikhilgadewal structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50 AT senthilkumarnachimuthu structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50 AT ashokkvarma structuralbasistostabilizethedomainmotionofbard1ardbrctbycstf50
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Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50

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