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Conformational states of the cytoprotective protein Bcl-xL

P. Ryzhov, Y. Tian, Y. Yao, A. A. Bobkov, View ORCID ProfileW. Im, F. M. Marassi
doi: https://doi.org/10.1101/2020.03.25.007740
P. Ryzhov
1Sanford Burnham Prebys Medical Discovery Institute
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Y. Tian
2Sanford-Burnham Medical Research Institute
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Y. Yao
3Sanford Burnham Medical Research Institute
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A. A. Bobkov
1Sanford Burnham Prebys Medical Discovery Institute
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W. Im
4Lehigh University
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  • ORCID record for W. Im
F. M. Marassi
1Sanford Burnham Prebys Medical Discovery Institute
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  • For correspondence: fmarassi@sbp.edu
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ABSTRACT

Bcl-xL is a major inhibitor of apoptosis, a fundamental homeostatic process of programmed cell death that is highly conserved across evolution. Because it plays prominent roles in cancer, Bcl-xL is a major target for anti-cancer therapy and for studies aimed at understanding its structure and activity. While Bcl-xL is active primarily at intracellular membranes, most studies have focused on soluble forms of the protein lacking both the membrane-anchoring C-terminal tail and the intrinsically disordered loop, and this has resulted in a fragmented view of the protein’s biological activity. Here we describe how these segments affect the protein’s conformation and ligand binding activity in both its soluble and membrane-anchored states. The combined data from nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and isothermal titration calorimetry (ITC) provide information about the molecular basis for the protein’s functionality and a view of its complex molecular mechanisms.

SIGNIFICANCE The human protein Bcl-xL is a key regulator of programmed cell death in health and disease. Structural studies, important for understating the molecular basis for its functions, have advanced primarily by deleting both the long disordered loop that regulates its activity and the C-terminal tail that anchors the protein to intracellular membranes Here we describe the preparation and conformations of full-length Bcl-xL in both its water-soluble and membrane-anchored states. The study provides new biophysical insights about Bcl-xL and its greater Bcl-2 protein family.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 25, 2020.
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Conformational states of the cytoprotective protein Bcl-xL
P. Ryzhov, Y. Tian, Y. Yao, A. A. Bobkov, W. Im, F. M. Marassi
bioRxiv 2020.03.25.007740; doi: https://doi.org/10.1101/2020.03.25.007740
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Conformational states of the cytoprotective protein Bcl-xL
P. Ryzhov, Y. Tian, Y. Yao, A. A. Bobkov, W. Im, F. M. Marassi
bioRxiv 2020.03.25.007740; doi: https://doi.org/10.1101/2020.03.25.007740

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