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Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation

The catalytic activity of human cytidine deaminase APOBEC3B (A3B) has been correlated with kataegic mutational patterns within multiple cancer types. The molecular basis of how the N-terminal non-catalytic CD1 regulates the catalytic activity and consequently, biological function of A3B remains rela...

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Autores principales: Xiao, Xiao, Yang, Hanjing, Arutiunian, Vagan, Fang, Yao, Besse, Guillaume, Morimoto, Cherie, Zirkle, Brett, Chen, Xiaojiang S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499559/
https://www.ncbi.nlm.nih.gov/pubmed/28575276
http://dx.doi.org/10.1093/nar/gkx362
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author Xiao, Xiao
Yang, Hanjing
Arutiunian, Vagan
Fang, Yao
Besse, Guillaume
Morimoto, Cherie
Zirkle, Brett
Chen, Xiaojiang S.
author_facet Xiao, Xiao
Yang, Hanjing
Arutiunian, Vagan
Fang, Yao
Besse, Guillaume
Morimoto, Cherie
Zirkle, Brett
Chen, Xiaojiang S.
author_sort Xiao, Xiao
collection PubMed
description The catalytic activity of human cytidine deaminase APOBEC3B (A3B) has been correlated with kataegic mutational patterns within multiple cancer types. The molecular basis of how the N-terminal non-catalytic CD1 regulates the catalytic activity and consequently, biological function of A3B remains relatively unknown. Here, we report the crystal structure of a soluble human A3B-CD1 variant and delineate several structural elements of CD1 involved in molecular assembly, nucleic acid interactions and catalytic regulation of A3B. We show that (i) A3B expressed in human cells exists in hypoactive high-molecular-weight (HMW) complexes, which can be activated without apparent dissociation into low-molecular-weight (LMW) species after RNase A treatment. (ii) Multiple surface hydrophobic residues of CD1 mediate the HMW complex assembly and affect the catalytic activity, including one tryptophan residue W127 that likely acts through regulating nucleic acid binding. (iii) One of the highly positively charged surfaces on CD1 is involved in RNA-dependent attenuation of A3B catalysis. (iv) Surface hydrophobic residues of CD1 are involved in heterogeneous nuclear ribonucleoproteins (hnRNPs) binding to A3B. The structural and biochemical insights described here suggest that unique structural features on CD1 regulate the molecular assembly and catalytic activity of A3B through distinct mechanisms.
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spelling pubmed-54995592017-07-10 Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation Xiao, Xiao Yang, Hanjing Arutiunian, Vagan Fang, Yao Besse, Guillaume Morimoto, Cherie Zirkle, Brett Chen, Xiaojiang S. Nucleic Acids Res Structural Biology The catalytic activity of human cytidine deaminase APOBEC3B (A3B) has been correlated with kataegic mutational patterns within multiple cancer types. The molecular basis of how the N-terminal non-catalytic CD1 regulates the catalytic activity and consequently, biological function of A3B remains relatively unknown. Here, we report the crystal structure of a soluble human A3B-CD1 variant and delineate several structural elements of CD1 involved in molecular assembly, nucleic acid interactions and catalytic regulation of A3B. We show that (i) A3B expressed in human cells exists in hypoactive high-molecular-weight (HMW) complexes, which can be activated without apparent dissociation into low-molecular-weight (LMW) species after RNase A treatment. (ii) Multiple surface hydrophobic residues of CD1 mediate the HMW complex assembly and affect the catalytic activity, including one tryptophan residue W127 that likely acts through regulating nucleic acid binding. (iii) One of the highly positively charged surfaces on CD1 is involved in RNA-dependent attenuation of A3B catalysis. (iv) Surface hydrophobic residues of CD1 are involved in heterogeneous nuclear ribonucleoproteins (hnRNPs) binding to A3B. The structural and biochemical insights described here suggest that unique structural features on CD1 regulate the molecular assembly and catalytic activity of A3B through distinct mechanisms. Oxford University Press 2017-07-07 2017-05-30 /pmc/articles/PMC5499559/ /pubmed/28575276 http://dx.doi.org/10.1093/nar/gkx362 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Structural Biology
Xiao, Xiao
Yang, Hanjing
Arutiunian, Vagan
Fang, Yao
Besse, Guillaume
Morimoto, Cherie
Zirkle, Brett
Chen, Xiaojiang S.
Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title_full Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title_fullStr Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title_full_unstemmed Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title_short Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation
title_sort structural determinants of apobec3b non-catalytic domain for molecular assembly and catalytic regulation
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499559/
https://www.ncbi.nlm.nih.gov/pubmed/28575276
http://dx.doi.org/10.1093/nar/gkx362
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