Exploring the conformational space of Bcl-2 protein variants: Dynamic contributions of the flexible loop domain and transmembrane region

Luis A. Caro-Gómez, Jorge L. Rosas-Trigueros, Edgar Mixcoha, José L. Vique-Sánchez, Humberto Gasperin-Sánchez, Claudia G. Benítez-Cardoza, Absalom Zamorano-Carrillo

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Resumen

Members of the Bcl-2 protein family regulate apoptosis through interactions with several proteins. A critical intrinsically disordered region (IDR) present in some members of the Bcl-2 family is essential for their function. Also, the structural and conformational plasticity of disordered regions is essential for the regulation of the Bcl-2 protein’s activity. Further, some proteins of the family contain transmembrane-helical regions, which anchor them into organelle membranes. Bcl-2, the archetypical member of the family, is characterized by an IDR labeled as a flexible loop domain (FLD) and a transmembrane domain (TMD). Another member of this family is the Bcl-2A1 protein, containing a TMD but lacking the FLD. To our knowledge, this is the first report which characterizes the individual and simultaneous dynamical contributions of FLD and TMD in Bcl-2 and Bcl-2A1 using molecular dynamics simulations (MDS). We examined the conformational spaces of Bcl-2, Bcl-2A1, and two artificial constructs lacking the TMD (Bcl-2∆TM and Bcl-2A1∆TM). As the results show, FLD and TMD stabilized each protein independently when they are present. When they coincided, such as in Bcl-2, an additive stabilizing effect is observed. This information is crucial for understanding the structural mechanisms of interaction in the Bcl-2 family.

Idioma originalInglés
Número de artículo3896
PublicaciónMolecules
Volumen24
N.º21
DOI
EstadoPublicada - 2019

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