The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1.
Bcl-2 plays a central role in the regulation of apoptosis. Structural studies of Bcl-2 revealed the presence of a flexible and natively disordered loop that bridges the Bcl-2 homology motifs, BH3 and BH4. This loop is phosphorylated on multiple sites in response to a variety of external stimuli, inc...
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doaj-c2c92d2f77784e9e8ccb104c8903353e2020-11-24T21:43:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01712e5204710.1371/journal.pone.0052047The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1.Congbao KangNagakumar BharathamJoel ChiaYuguang MuKwanghee BaekHo Sup YoonBcl-2 plays a central role in the regulation of apoptosis. Structural studies of Bcl-2 revealed the presence of a flexible and natively disordered loop that bridges the Bcl-2 homology motifs, BH3 and BH4. This loop is phosphorylated on multiple sites in response to a variety of external stimuli, including the microtubule-targeting drugs, paclitaxel and colchicine. Currently, the underlying molecular mechanism of Bcl-2 phosphorylation and its biological significance remain elusive. In this study, we investigated the molecular characteristics of this anti-apoptotic protein. To this end, we generated synthetic peptides derived from the Bcl-2 loop, and multiple Bcl-2 loop truncation mutants that include the phosphorylation sites. Our results demonstrate that S87 in the flexible loop of Bcl-2 is the primary phosphorylation site for JNK and ERK2, suggesting some sequence or structural specificity for the phosphorylation by these kinases. Our NMR studies and molecular dynamics simulation studies support indicate that phosphorylation of S87 induces a conformational change in the peptide. Finally, we show that the phosphorylated peptides of the Bcl-2 loop can bind Pin1, further substantiating the phosphorylation-mediated conformation change of Bcl-2.http://europepmc.org/articles/PMC3525568?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Congbao Kang Nagakumar Bharatham Joel Chia Yuguang Mu Kwanghee Baek Ho Sup Yoon |
spellingShingle |
Congbao Kang Nagakumar Bharatham Joel Chia Yuguang Mu Kwanghee Baek Ho Sup Yoon The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. PLoS ONE |
author_facet |
Congbao Kang Nagakumar Bharatham Joel Chia Yuguang Mu Kwanghee Baek Ho Sup Yoon |
author_sort |
Congbao Kang |
title |
The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. |
title_short |
The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. |
title_full |
The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. |
title_fullStr |
The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. |
title_full_unstemmed |
The natively disordered loop of Bcl-2 undergoes phosphorylation-dependent conformational change and interacts with Pin1. |
title_sort |
natively disordered loop of bcl-2 undergoes phosphorylation-dependent conformational change and interacts with pin1. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
Bcl-2 plays a central role in the regulation of apoptosis. Structural studies of Bcl-2 revealed the presence of a flexible and natively disordered loop that bridges the Bcl-2 homology motifs, BH3 and BH4. This loop is phosphorylated on multiple sites in response to a variety of external stimuli, including the microtubule-targeting drugs, paclitaxel and colchicine. Currently, the underlying molecular mechanism of Bcl-2 phosphorylation and its biological significance remain elusive. In this study, we investigated the molecular characteristics of this anti-apoptotic protein. To this end, we generated synthetic peptides derived from the Bcl-2 loop, and multiple Bcl-2 loop truncation mutants that include the phosphorylation sites. Our results demonstrate that S87 in the flexible loop of Bcl-2 is the primary phosphorylation site for JNK and ERK2, suggesting some sequence or structural specificity for the phosphorylation by these kinases. Our NMR studies and molecular dynamics simulation studies support indicate that phosphorylation of S87 induces a conformational change in the peptide. Finally, we show that the phosphorylated peptides of the Bcl-2 loop can bind Pin1, further substantiating the phosphorylation-mediated conformation change of Bcl-2. |
url |
http://europepmc.org/articles/PMC3525568?pdf=render |
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