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Trends Biochem Sci. 2015 Dec;40(12):736-748. doi: 10.1016/j.tibs.2015.09.007. Epub 2015 Nov 3.

Redefining the BH3 Death Domain as a 'Short Linear Motif'.

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Molecular Biology of the Cell Laboratory, Ecole Normale Supérieure de Lyon, UMR 5239, CNRS-UCBL-ENS Lyon, 46 Allée d'Italie, 69364 Lyon cedex 07, France. Electronic address:
Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086, CNRS, Université Lyon 1, IBCP - 7 passage du Vercors, 69367 Lyon cedex 07, France; Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052, CNRS 5286, Centre Léon Bérard, Université Lyon 1, 151 cours Albert Thomas, 69424 Lyon cedex 03, France.
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary; VIB Structural Biology Research Center (SBRC), Vrije Universiteit Brussel, Brussels 1050, Belgium.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address:


B cell lymphoma-2 (BCL-2)-related proteins control programmed cell death through a complex network of protein-protein interactions mediated by BCL-2 homology 3 (BH3) domains. Given their roles as dynamic linchpins, the discovery of novel BH3-containing proteins has attracted considerable attention. However, without a clearly defined BH3 signature sequence the BCL-2 family has expanded to include a nebulous group of nonhomologous BH3-only proteins, now justified by an intriguing twist. We present evidence that BH3s from both ordered and disordered proteins represent a new class of short linear motifs (SLiMs) or molecular recognition features (MoRFs) and are diverse in their evolutionary histories. The implied corollaries are that BH3s have a broad phylogenetic distribution and could potentially bind to non-BCL-2-like structural domains with distinct functions.


BCL-2 family; BH3; MoRF/MoRE; SLiM; globular domains; intrinsically disordered proteins

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