TY - JOUR
T1 - Conserved dynamic mechanism of allosteric response to l-arg in divergent bacterial arginine repressors
AU - Pandey, Saurabh Kumar
AU - Melichercik, Milan
AU - Rěha, David
AU - Ettrich, Rüdiger H.
AU - Carey, Jannette
N1 - Funding Information:
This research was funded by the Czech Science Foundation [13-21053S; http://www.gacr.cz/] and by an MoA between the Institute of Microbiology, Czech Academy of Sciences, and the College of Biomedical Sciences, Larkin University. M.M. and S.K.P. were supported by the Slovak Research and Development Agency, Contract APVV-16-0600. Access to instruments and other facilities was supported by the Czech Research Infrastructure for Systems Biology C4SYS [LM2015055] and the National Grid Infrastructure MetaCentrum, [LM2010005]. J.C. gratefully acknowledges support from U.S. National Science Foundation awards DBI13-58737 and DBI16-59726. The Article Processing Charge was funded by Larkin University
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Hexameric arginine repressor, ArgR, is the feedback regulator of bacterial L-arginine regulons, and sensor of L-arg that controls transcription of genes for its synthesis and catabolism. Although ArgR function, as well as its secondary, tertiary, and quaternary structures, is essentially the same in E. coli and B. subtilis, the two proteins differ significantly in sequence, including residues implicated in the response to L-arg. Molecular dynamics simulations are used here to evaluate the behavior of intact B. subtilis ArgR with and without L-arg, and are compared with prior MD results for a domain fragment of E. coli ArgR. Relative to its crystal structure, B. subtilis ArgR in absence of L-arg undergoes a large-scale rotational shift of its trimeric subassemblies that is very similar to that observed in the E. coli protein, but the residues driving rotation have distinct secondary and tertiary structural locations, and a key residue that drives rotation in E. coli is missing in B. subtilis. The similarity of trimer rotation despite different driving residues suggests that a rotational shift between trimers is integral to ArgR function. This conclusion is supported by phylogenetic analysis of distant ArgR homologs reported here that indicates at least three major groups characterized by distinct sequence motifs but predicted to undergo a common rotational transition. The dynamic consequences of L-arg binding for transcriptional activation of intact ArgR are evaluated here for the first time in two-microsecond simulations of B. subtilis ArgR. L-arg binding to intact B. subtilis ArgR causes a significant further shift in the angle of rotation between trimers that causes the N-terminal DNA-binding domains lose their interactions with the C-terminal domains, and is likely the first step toward adopting DNA-binding-competent conformations. The results aid interpretation of crystal structures of ArgR and ArgR-DNA complexes.
AB - Hexameric arginine repressor, ArgR, is the feedback regulator of bacterial L-arginine regulons, and sensor of L-arg that controls transcription of genes for its synthesis and catabolism. Although ArgR function, as well as its secondary, tertiary, and quaternary structures, is essentially the same in E. coli and B. subtilis, the two proteins differ significantly in sequence, including residues implicated in the response to L-arg. Molecular dynamics simulations are used here to evaluate the behavior of intact B. subtilis ArgR with and without L-arg, and are compared with prior MD results for a domain fragment of E. coli ArgR. Relative to its crystal structure, B. subtilis ArgR in absence of L-arg undergoes a large-scale rotational shift of its trimeric subassemblies that is very similar to that observed in the E. coli protein, but the residues driving rotation have distinct secondary and tertiary structural locations, and a key residue that drives rotation in E. coli is missing in B. subtilis. The similarity of trimer rotation despite different driving residues suggests that a rotational shift between trimers is integral to ArgR function. This conclusion is supported by phylogenetic analysis of distant ArgR homologs reported here that indicates at least three major groups characterized by distinct sequence motifs but predicted to undergo a common rotational transition. The dynamic consequences of L-arg binding for transcriptional activation of intact ArgR are evaluated here for the first time in two-microsecond simulations of B. subtilis ArgR. L-arg binding to intact B. subtilis ArgR causes a significant further shift in the angle of rotation between trimers that causes the N-terminal DNA-binding domains lose their interactions with the C-terminal domains, and is likely the first step toward adopting DNA-binding-competent conformations. The results aid interpretation of crystal structures of ArgR and ArgR-DNA complexes.
KW - Entropy
KW - Global motion
KW - Ligand binding
KW - Molecular evolution
KW - Salt bridges
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U2 - 10.3390/molecules25092247
DO - 10.3390/molecules25092247
M3 - Article
C2 - 32397647
AN - SCOPUS:85084466508
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 9
M1 - 2247
ER -