Dynamics of the BH3-Only Protein Binding Interface of Bcl-xL.
The balance and interplay between pro-death and pro-survival members of the B-cell lymphoma-2 (Bcl-2) family proteins play key roles in regulation of the mitochondrial pathway of programmed cell death. Recent NMR and biochemical studies have revealed that binding of the proapoptotic BH3-only protein PUMA induces significant unfolding of antiapoptotic Bcl-xL at the interface, which in turn disrupts the Bcl-xL/p53 interaction to activate apoptosis. However, the molecular mechanism of such regulated unfolding of Bcl-xL is not fully understood. Analysis of the existing Protein Data Bank structures of Bcl-xL in both bound and unbound states reveal substantial intrinsic heterogeneity at its BH3-only protein binding interface. Large-scale atomistic simulations were performed in explicit solvent for six representative structures to further investigate the intrinsic conformational dynamics of Bcl-xL. The results support that the BH3-only protein binding interface of Bcl-xL is much more dynamic compared to the rest of the protein, both unbound and when bound to various BH3-only proteins. Such intrinsic interfacial conformational dynamics likely provides a physical basis that allows Bcl-xL to respond sensitively to detailed biophysical properties of the ligand. The ability of Bcl-xL to retain or even enhance dynamics at the interface in bound states could further facilitate the regulation of its interactions with various BH3-only proteins such as through posttranslational modifications.
Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas.
Xiaorong
X
Liu
Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas.
Alex
A
Beugelsdijk
Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas. Electronic address: jianhanc@ksu.edu.
Jianhan
J
Chen
D030562:Databases, Protein; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism*
D051020:bcl-X Protein