Innate Conformational Dynamics Drive Binding Specificity in Anti-Apoptotic Proteins Mcl-1 and Bcl-2.
Biochemistry
; 62(11): 1619-1630, 2023 06 06.
Article
em En
| MEDLINE
| ID: mdl-37192192
ABSTRACT
The structurally conserved B-cell lymphoma 2 (Bcl-2) family of protein function to promote or inhibit apoptosis through an exceedingly complex web of specific, intrafamilial protein-protein interactions. The critical role of these proteins in lymphomas and other cancers has motivated a widespread interest in understanding the molecular mechanisms that drive specificity in Bcl-2 family interactions. However, the high degree of structural similarity among Bcl-2 homologues has made it difficult to rationalize the highly specific (and often divergent) binding behavior exhibited by these proteins using conventional structural arguments. In this work, we use time-resolved hydrogen deuterium exchange mass spectrometry to explore shifts in conformational dynamics associated with binding partner engagement in the Bcl-2 family proteins Bcl-2 and Mcl-1. Using this approach combined with homology modeling, we reveal that Mcl-1 binding is driven by a large-scale shift in conformational dynamics, while Bcl-2 complexation occurs primarily through a classical charge compensation mechanism. This work has implications for understanding the evolution of internally regulated biological systems composed of structurally similar proteins and for the development of drugs targeting Bcl-2 family proteins for promotion of apoptosis in cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
/
Proteínas Reguladoras de Apoptose
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article