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The antiprion compound 6-aminophenanthridine inhibits the protein folding
activity of the ribosome by direct competition
#MMPMID23673663
Pang Y
; Kurella S
; Voisset C
; Samanta D
; Banerjee D
; Schabe A
; Das Gupta C
; Galons H
; Blondel M
; Sanyal S
J Biol Chem
2013[Jun]; 288
(26
): 19081-9
PMID23673663
show ga
Domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the
active center for the protein folding activity of the ribosome (PFAR). Using in
vitro transcribed domain V rRNAs from Escherichia coli and Saccharomyces
cerevisiae as the folding modulators and human carbonic anhydrase as a model
protein, we demonstrate that PFAR is conserved from prokaryotes to eukaryotes. It
was shown previously that 6-aminophenanthridine (6AP), an antiprion compound,
inhibits PFAR. Here, using UV cross-linking followed by primer extension, we show
that the protein substrates and 6AP interact with a common set of nucleotides on
domain V of 23S rRNA. Mutations at the interaction sites decreased PFAR and
resulted in loss or change of the binding pattern for both the protein substrates
and 6AP. Moreover, kinetic analysis of human carbonic anhydrase refolding showed
that 6AP decreased the yield of the refolded protein but did not affect the rate
of refolding. Thus, we conclude that 6AP competitively occludes the protein
substrates from binding to rRNA and thereby inhibits PFAR. Finally, we propose a
scheme clarifying the mechanism by which 6AP inhibits PFAR.
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