Conformational States of the Cytoprotective Protein Bcl-xL

• Published in: Biophysical journal 2020-10, Vol.119 (7), p.1324-1334
• Main Authors: Ryzhov, Pavel, Tian, Ye, Yao, Yong, Bobkov, Andrey A., Im, Wonpil, Marassi, Francesca M.
• Format: Article
• Language: English
• Subjects: Apoptosis; bcl-X Protein; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Protein Conformation
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2020.08.014

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 anticancer therapy and for studies aimed at understanding its structure and activity. Although 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 the conformation of full-length Bcl-xL. Using NMR spectroscopy, molecular dynamics simulations, and isothermal titration calorimetry, we show how the three structural elements affect the protein’s structure, dynamics, and ligand-binding activity in both its soluble and membrane-anchored states. The combined data provide information about the molecular basis for the protein’s functionality and a view of its complex molecular mechanisms.