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

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 interactions are mediated by evolutionarily diverse BH3 motifs to regulate apoptosis. Given their key roles, BH3 mimetics are in clinical trials as cancer therapies.The discovery of novel BH3-only proteins represents a major endeavor in the cell death field. As a result, BH3 motifs are reportedly present in a nebulous conglomerate of different proteins, both structured and intrinsically disordered.There is no rigorous definition of a BH3 motif. Currently available BH3 signatures are diverse and elusive for predicting new functional BH3-containing proteins.Redefining the BH3 motif as a new type of short linear motif (SLiM) or molecular recognition feature (MoRF) reconciles many puzzling features of this motif and opens up new avenues for research.