Exploring the Conformational Space of Bcl-2 Protein Variants: Dynamic Contributions of the Flexible Loop Domain and Transmembrane Region.

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

doi:10.3390/molecules24213896

Abstract

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-2ΔTM and Bcl-2A1ΔTM). 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.

Highlights

All multicellular organisms must maintain precise regulation of their cell mass turnover during the entirety of their lifespan to avoid a variety of health disorders such as cancer, autoimmunity, and neurodegenerative dysfunction
To the best of our knowledge, here, we have described, for the first time, the combined participation of flexible loop domain (FLD) and transmembrane domain (TMD) regions by exploring the conformational space of Bcl-2, Bcl-2A1, and two artificial constructs lacking the C-terminal domain
The BH domains were similarity between them

Summary

Introduction

All multicellular organisms must maintain precise regulation of their cell mass turnover during the entirety of their lifespan to avoid a variety of health disorders such as cancer, autoimmunity, and neurodegenerative dysfunction. Damaged or unwanted cells are eliminated by one of the several types of programmed cell death, with apoptosis being the most common process in mammals [1,2,3]. The mutual interactions among Bcl-2 family protein members regulate these events [4,5,6]. This family is composed of proteins that either impede (anti-apoptotic) or promote (pro-apoptotic) apoptosis, or regulate pro- and anti-apoptotic members of the family [7,8,9].

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Conclusion