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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