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Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape

Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic fac...

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Autores principales: Ratnasinghe, Brian D., Haque, Neshatul, Wagenknecht, Jessica B., Jensen, Davin R., Esparza, Guadalupe V., Leverence, Elise N., De Assuncao, Thiago Milech, Mathison, Angela J., Lomberk, Gwen, Smith, Brian C., Volkman, Brian F., Urrutia, Raul, Zimmermann, Michael T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189839/
https://www.ncbi.nlm.nih.gov/pubmed/37207265
http://dx.doi.org/10.1101/2023.04.28.536249
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author Ratnasinghe, Brian D.
Haque, Neshatul
Wagenknecht, Jessica B.
Jensen, Davin R.
Esparza, Guadalupe V.
Leverence, Elise N.
De Assuncao, Thiago Milech
Mathison, Angela J.
Lomberk, Gwen
Smith, Brian C.
Volkman, Brian F.
Urrutia, Raul
Zimmermann, Michael T.
author_facet Ratnasinghe, Brian D.
Haque, Neshatul
Wagenknecht, Jessica B.
Jensen, Davin R.
Esparza, Guadalupe V.
Leverence, Elise N.
De Assuncao, Thiago Milech
Mathison, Angela J.
Lomberk, Gwen
Smith, Brian C.
Volkman, Brian F.
Urrutia, Raul
Zimmermann, Michael T.
author_sort Ratnasinghe, Brian D.
collection PubMed
description Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation.
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spelling pubmed-101898392023-05-18 Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape Ratnasinghe, Brian D. Haque, Neshatul Wagenknecht, Jessica B. Jensen, Davin R. Esparza, Guadalupe V. Leverence, Elise N. De Assuncao, Thiago Milech Mathison, Angela J. Lomberk, Gwen Smith, Brian C. Volkman, Brian F. Urrutia, Raul Zimmermann, Michael T. bioRxiv Article Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation. Cold Spring Harbor Laboratory 2023-04-28 /pmc/articles/PMC10189839/ /pubmed/37207265 http://dx.doi.org/10.1101/2023.04.28.536249 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Ratnasinghe, Brian D.
Haque, Neshatul
Wagenknecht, Jessica B.
Jensen, Davin R.
Esparza, Guadalupe V.
Leverence, Elise N.
De Assuncao, Thiago Milech
Mathison, Angela J.
Lomberk, Gwen
Smith, Brian C.
Volkman, Brian F.
Urrutia, Raul
Zimmermann, Michael T.
Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title_full Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title_fullStr Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title_full_unstemmed Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title_short Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
title_sort beyond structural bioinformatics for genomics with dynamics characterization of an expanded kras mutational landscape
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189839/
https://www.ncbi.nlm.nih.gov/pubmed/37207265
http://dx.doi.org/10.1101/2023.04.28.536249
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