Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Poster Session I

1-POS Board 1 Evidence for a Broader Definition of BH3 Motifs Previously Known to Exist Only in Disordered and Globular Apoptosis Regulators Abdel Aouacheria 1 , Christophe Combet 2 , J. Marie Hardwick 3 . 1 ENS Lyon CNRS UMR5239 Molecular Biology of the Cell Laboratory, Lyon, France, 2 CNRS UMR5086 Institute of Biology and Chemistry of Proteins, Lyon, France, 3 Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. BCL-2 proteins control cell death by apoptosis through a complex network of protein-protein interactions. This protein group is formed by a family of homologs related to BCL-2 (which contain BH1, BH2 and BH3 motifs), and by BH3-only proteins, which bind tightly to the BCL- 2-like family members via their BH3 motif. Pro-apoptotic and anti-apoptotic BCL-2 homologs promote or prevent mitochondrial disruption, whereas classical BH3-only proteins (seven in humans, excluding Bid) act upstream of mitochondria to connect various stress stimuli to the BCL-2-regulated apoptotic pathway. BH3 motifs have three notable features, (1) a short length of about 20 amino acids, (2) a loose consensus sequence, and (3) they are present both in proteins adopting (or predicted to adopt) a defined 3D fold, such as the globular protein BCL-2, and in intrinsically disordered proteins (IDPs) such as the seven classical BH3-only proteins. In the unstructured BH3-only proteins, the BH3 motif is located in the context of disordered regions and adopts an alpha-helical structure upon binding to the BCL-2 globular domain, whereas in BCL-2 and its homologs, the BH3 motif is contained within an amphipathic alpha-helix that contributes to the overall domain architecture. Furthermore, the BH3 motif is not only involved in protein-protein interactions of intrinsically disordered BH3-only proteins with BCL-2-like globular domains but also in protein-protein interactions between globular domains (of the BCL- 2-type). BCL-2 homologous proteins thus represent binding sites (receptors) for BH3 motifs, whether embodied in another BCL-2 homolog or within an IDP. Based on these features, we provide computational analyses of publicly available protein sequences and experimental evidence that the BH3 motif is a functional entity of broader scope not specific to BCL-2 proteins or cell death regulators.

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