Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation
Mushtaq, Ameeq Ul ; Ådén, Jörgen ; Clifton, Luke A. ; Wacklin-Knecht, Hanna LU
; Campana, Mario
; Dingeldein, Artur P.G.
; Persson, Cecilia
; Sparrman, Tobias
and Gröbner, Gerhard
(2021)
In Communications Biology
4(1).
- Abstract
B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane... (More)
B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.
(Less)
- author
- Mushtaq, Ameeq Ul
; Ådén, Jörgen
; Clifton, Luke A.
; Wacklin-Knecht, Hanna
LU
; Campana, Mario
; Dingeldein, Artur P.G.
; Persson, Cecilia
; Sparrman, Tobias
and Gröbner, Gerhard
- organization
- publishing date
- 2021-04-27
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Communications Biology
- volume
- 4
- issue
- 1
- article number
- 507
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:33907308
- scopus:85105112344
- ISSN
- 2399-3642
- DOI
- 10.1038/s42003-021-02032-1
- language
- English
- LU publication?
- yes
- id
- 452bcb7c-b355-4dba-af7c-3d1cc6d694fd
- date added to LUP
- 2021-05-20 15:08:18
- date last changed
- 2024-08-24 18:18:36
@article{452bcb7c-b355-4dba-af7c-3d1cc6d694fd,
abstract = {{<p>B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.</p>}},
author = {{Mushtaq, Ameeq Ul and Ådén, Jörgen and Clifton, Luke A. and Wacklin-Knecht, Hanna and Campana, Mario and Dingeldein, Artur P.G. and Persson, Cecilia and Sparrman, Tobias and Gröbner, Gerhard}},
issn = {{2399-3642}},
language = {{eng}},
month = {{04}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Communications Biology}},
title = {{Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation}},
url = {{http://dx.doi.org/10.1038/s42003-021-02032-1}},
doi = {{10.1038/s42003-021-02032-1}},
volume = {{4}},
year = {{2021}},
}