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A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis

Bromodomains (BRDs) are small protein interaction modules of about 110 amino acids that selectively recognize acetylated lysine in histones and other proteins. These domains have been identified in a variety of multi-domain proteins involved in transcriptional regulation or chromatin remodeling in e...

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Autores principales: Novak, Leonore, Petrosino, Maria, Santorelli, Daniele, Chiaraluce, Roberta, Consalvi, Valerio, Pasquo, Alessandra, Travaglini-Allocatelli, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199192/
https://www.ncbi.nlm.nih.gov/pubmed/34073056
http://dx.doi.org/10.3390/ijms22115953
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author Novak, Leonore
Petrosino, Maria
Santorelli, Daniele
Chiaraluce, Roberta
Consalvi, Valerio
Pasquo, Alessandra
Travaglini-Allocatelli, Carlo
author_facet Novak, Leonore
Petrosino, Maria
Santorelli, Daniele
Chiaraluce, Roberta
Consalvi, Valerio
Pasquo, Alessandra
Travaglini-Allocatelli, Carlo
author_sort Novak, Leonore
collection PubMed
description Bromodomains (BRDs) are small protein interaction modules of about 110 amino acids that selectively recognize acetylated lysine in histones and other proteins. These domains have been identified in a variety of multi-domain proteins involved in transcriptional regulation or chromatin remodeling in eukaryotic cells. BRD inhibition is considered an attractive therapeutic approach in epigenetic disorders, particularly in oncology. Here, we present a Φ value analysis to investigate the folding pathway of the second domain of BRD2 (BRD2(2)). Using an extensive mutational analysis based on 25 site-directed mutants, we provide structural information on both the intermediate and late transition state of BRD2(2). The data reveal that the C-terminal region represents part of the initial folding nucleus, while the N-terminal region of the domain consolidates its structure only later in the folding process. Furthermore, only a small number of native-like interactions have been identified, suggesting the presence of a non-compact, partially folded state with scarce native-like characteristics. Taken together, these results indicate that, in BRD2(2), a hierarchical mechanism of protein folding can be described with non-native interactions that play a significant role in folding.
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spelling pubmed-81991922021-06-14 A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis Novak, Leonore Petrosino, Maria Santorelli, Daniele Chiaraluce, Roberta Consalvi, Valerio Pasquo, Alessandra Travaglini-Allocatelli, Carlo Int J Mol Sci Article Bromodomains (BRDs) are small protein interaction modules of about 110 amino acids that selectively recognize acetylated lysine in histones and other proteins. These domains have been identified in a variety of multi-domain proteins involved in transcriptional regulation or chromatin remodeling in eukaryotic cells. BRD inhibition is considered an attractive therapeutic approach in epigenetic disorders, particularly in oncology. Here, we present a Φ value analysis to investigate the folding pathway of the second domain of BRD2 (BRD2(2)). Using an extensive mutational analysis based on 25 site-directed mutants, we provide structural information on both the intermediate and late transition state of BRD2(2). The data reveal that the C-terminal region represents part of the initial folding nucleus, while the N-terminal region of the domain consolidates its structure only later in the folding process. Furthermore, only a small number of native-like interactions have been identified, suggesting the presence of a non-compact, partially folded state with scarce native-like characteristics. Taken together, these results indicate that, in BRD2(2), a hierarchical mechanism of protein folding can be described with non-native interactions that play a significant role in folding. MDPI 2021-05-31 /pmc/articles/PMC8199192/ /pubmed/34073056 http://dx.doi.org/10.3390/ijms22115953 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Novak, Leonore
Petrosino, Maria
Santorelli, Daniele
Chiaraluce, Roberta
Consalvi, Valerio
Pasquo, Alessandra
Travaglini-Allocatelli, Carlo
A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title_full A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title_fullStr A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title_full_unstemmed A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title_short A Glimpse into the Structural Properties of the Intermediate and Transition State in the Folding of Bromodomain 2 Domain 2 by Φ Value Analysis
title_sort glimpse into the structural properties of the intermediate and transition state in the folding of bromodomain 2 domain 2 by φ value analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199192/
https://www.ncbi.nlm.nih.gov/pubmed/34073056
http://dx.doi.org/10.3390/ijms22115953
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