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

Abdel Aouacheria, Christophe Combet, Peter Tompa, J. Marie Hardwick

Research output: Contribution to journalReview articlepeer-review

32 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)736-748
Number of pages13
JournalTrends in biochemical sciences
Issue number12
StatePublished - 2015


  • BCL-2 family
  • BH3
  • Globular domains
  • Intrinsically disordered proteins
  • MoRF/MoRE
  • SLiM

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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