skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1372228
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nucleic Acids Research; Journal Volume: 45; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Xiao, Xiao, Yang, Hanjing, Arutiunian, Vagan, Fang, Yao, Besse, Guillaume, Morimoto, Cherie, Zirkle, Brett, and Chen, Xiaojiang S. Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. United States: N. p., 2017. Web. doi:10.1093/nar/gkx362.
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. United States. doi:10.1093/nar/gkx362.
Xiao, Xiao, Yang, Hanjing, Arutiunian, Vagan, Fang, Yao, Besse, Guillaume, Morimoto, Cherie, Zirkle, Brett, and Chen, Xiaojiang S. Tue . "Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation". United States. doi:10.1093/nar/gkx362.
@article{osti_1372228,
title = {Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation},
author = {Xiao, Xiao and Yang, Hanjing and Arutiunian, Vagan and Fang, Yao and Besse, Guillaume and Morimoto, Cherie and Zirkle, Brett and Chen, Xiaojiang S.},
abstractNote = {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.},
doi = {10.1093/nar/gkx362},
journal = {Nucleic Acids Research},
number = 12,
volume = 45,
place = {United States},
year = {Tue May 30 00:00:00 EDT 2017},
month = {Tue May 30 00:00:00 EDT 2017}
}