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Review
. 2008 Dec;27 Suppl 1(Suppl 1):S137-48.
doi: 10.1038/onc.2009.51.

The autophagy effector Beclin 1: a novel BH3-only protein

Affiliations
Review

The autophagy effector Beclin 1: a novel BH3-only protein

S Sinha et al. Oncogene. 2008 Dec.

Abstract

BH3 domains were originally discovered in the context of apoptosis regulators and they mediate binding of proapoptotic Bcl-2 family members to antiapoptotic Bcl-2 family members. Yet, recent studies indicate that BH3 domains do not function uniquely in apoptosis regulation; they also function in the regulation of another critical pathway involved in cellular and tissue homeostasis called autophagy. Antiapoptotic Bcl-2 homologs downregulate autophagy through interactions with the essential autophagy effector and haploinsufficient tumor suppressor, Beclin 1. Beclin 1 contains a BH3 domain, similar to that of Bcl-2 proteins, which is necessary and sufficient for binding to antiapoptotic Bcl-2 homologs and required for Bcl-2-mediated inhibition of autophagy. This review will summarize the evidence that the BH3 domain of Beclin 1 serves as a key structural motif that enables Bcl-2 to function not only as an antiapoptotic protein, but also as an antiautophagy protein.

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Conflict of interest statement

Conflict of interest

The authors have declared no conflict of interest.

Figures

Figure 1
Figure 1
Comparison of BH3 domains from Beclin 1 and different proapoptotic proteins. (a) Sequence alignment. Backgrounds of conserved residues are colored by residue type: yellow hydrophobic, green small, blue basic and red acidic. (b) Structural superposition. BH3 domains are represented by different colored ribbons; Beclin 1 (dark green,); Bad (violet) and Bak (teal). Residues conserved among BH3 domains that are involved in binding to the antiapoptotic Bcl-2 homologs are shown in atomic detail. All molecular figures were prepared with the program PYMOL (http://www.pymol.org).
Figure 2
Figure 2
Bindingof BH3 domains to Bcl-2 homologs. Molecular surfaces of M11 and Bcl- XL are colored by atom type—oxygen red, nitrogen blue, sulfur green and carbon gray. BH3 domains are displayed in dark green ribbon with conserved residues involved in binding to antiapoptotic Bcl-2 homologs shown in atomic detail (a) Bad bound to Bcl-XL. (b) Beclin 1 bound to Bcl-XL. (c) Beclin 1 bound to M11.
Figure 3
Figure 3
Schematic representation of the role of the Beclin 1 BH3 domain in the regulation of autophagy. The vesicle nucleation complex consists of Vps34 (also known as class III PI3K) and activators, such as Beclin 1, either Atg14 or UVRAG, Ambra1 and Bif-1. The binding of Bcl-2 homologs to the BH3 domain of Beclin 1 prevents the assembly of an autophagy-competent complex (left). Disruption of the Beclin 1–Bcl-2 homolog interaction , either by competitive displacement of the Beclin 1 BH3 domain by other BH3 domain-containing proteins (upper right) or due to JNK1-mediated phosphorylation of Bcl-2 (lower right) results in the assembly of an autophagy-competent complex. The lipid kinase activity of this complex then catalyses the conversion of PI to PI3P (shown with violet circles) resulting in autophagy.

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