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2017 ; 11
(ä): 99-104
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Unveiling the folding mechanism of the Bromodomains
#MMPMID28955774
Petrosino M
; Bonetti D
; Pasquo A
; Lori L
; Chiaraluce R
; Consalvi V
; Travaglini-Allocatelli C
Biochem Biophys Rep
2017[Sep]; 11
(ä): 99-104
PMID28955774
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Bromodomains (BRDs) are small protein domains often present in large multidomain
proteins involved in transcriptional regulation in eukaryotic cells. They
currently represent valuable targets for the development of inhibitors of
aberrant transcriptional processes in a variety of human diseases. Here we report
urea-induced equilibrium unfolding experiments monitored by circular dichroism
(CD) and fluorescence on two structurally similar BRDs: BRD2(2) and BRD4(1),
showing that BRD4(1) is more stable than BRD2(2). Moreover, we report a
description of their kinetic folding mechanism, as obtained by careful analysis
of stopped-flow and temperature-jump data. The presence of a high energy
intermediate for both proteins, suggested by the non-linear dependence of the
folding rate on denaturant concentration in the millisec time regime, has been
experimentally observed by temperature-jump experiments. Quantitative global
analysis of all the rate constants obtained over a wide range of urea
concentrations, allowed us to propose a common, three-state, folding mechanism
for these two BRDs. Interestingly, the intermediate of BRD4(1) appears to be more
stable and structurally native-like than that populated by BRD2(2). Our results
underscore the role played by structural topology and sequence in determining and
tuning the folding mechanism.
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