Review
There is more to life and death than mitochondria: Bcl-2 proteins at the
endoplasmic reticulum
Matthew G. Annis
a
, Jeremy A. Yethon
a
, Brian Leber
b
, David W. Andrews
a,
*
a
Department of Biochemistry, McMaster University Medical Centre, McMaster University, 1200 Main St W., Hamilton, ON, Canada L8N 3Z5
b
Departments of Biochemistry and Medicine, McMaster University Medical Centre, McMaster University, Hamilton, ON, Canada L8N 3Z5
Received 28 April 2003; accepted 15 July 2003
Abstract
Proteins of the Bcl-2 family are important regulators of cell fate. The role of these proteins in controlling mitochondrial apoptotic
processes has been extensively investigated, although exact molecular mechanisms are incompletely understood. However, mounting
evidence indicates that these proteins also function at the endoplasmic reticulum and other locations within the cell. Both pro- and anti-
apoptotic Bcl-2 family members can regulate endoplasmic reticulum calcium, cellular pH and endoplasmic reticulum resident proteins. In this
review, we discuss the activities and potential targets of Bcl-2 family members at the endoplasmic reticulum and other cellular locations.
D 2003 Elsevier B.V. All rights reserved.
Keywords: Bcl-2; Endoplasmic reticulum; Calcium; Bap31; Bax
1. Introduction
The Bcl-2 family of proteins can be separated into two
functional categories, either pro- or anti-apoptotic (recently
reviewed in Ref. [1]). Although cellular functions for these
proteins are well recognized, the precise molecular mecha-
nism by which these proteins regulate cell death (either
positively or negatively) is controversial and the subject of
many ongoing investigations. To be designated as a Bcl-2
family member, a protein must possess at least one of the
four conserved Bcl-2 homology (BH) domains and have a
demonstrable effect on apoptosis. Interactions between
family members mediated by BH domains are critical for
many aspects of their function. However, the sequence
diversity of these proteins suggests a level of diversity in
function that has not been fully explored: indeed, the
number of both pro- and anti-apoptotic members exceeds
those needed even in current models of multi-step regulation
of apoptosis (e.g. Ref. [2]).
The three-dimensional structure of Bcl-X
L
[3],Bid[4],
Bax [5], Bcl-2 [6], and Bcl-w [7,8] are more similar than
predicted from primary sequence alignments. Each protein
has two central hydrophobic helices surrounded by amphi-
pathic helices in a structure that resembles the pore-forming
domain of the bacterial diphtheria toxin. Consistent with the
known structures, there is good in vitro evidence that some
of these proteins can form pores or channels in lipid bilayers
(reviewed in Ref. [9]). Thus, a combination of protein:pro-
tein interactions and pore/channel formation are postulated
to constitute the main molecular mechanisms of Bcl-2
activity. Since many of the Bcl-2 family members have
similar structures, the sequence diversity may determine
subtle aspects of the regulation of these proteins through
specific protein:protein interactions.
Bcl-2, the prototype for the Bcl-2 family, contains all
four BH domains (BH1 –4) and a carboxyl-terminal hydro-
phobic sequence called a tail-anchor. Unlike many other
tail-anchor proteins which are targeted to a single subcellu-
lar location, Bcl-2 is localized to the endoplasmic reticulum
(ER), nuclear envelope, and outer mitochondrial membrane
in mammalian cells [10]. This broad localization allows Bcl-
2 to function at spatially distinct regions of the cell, thereby
enhancing its anti-apoptotic activity. The discovery that Bcl-
2 targets via a tail-anchor sequence occurred at roughly the
same time as the elucidation of the mechanisms that regulate
targeting and integration of tail-anchor sequences in subcel-
lular membranes [11,12]. These studies suggested that it
0167-4889/$ - see front matter D 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbamcr.2003.07.001
* Corresponding author. Tel.: +1-905-525-9140x22075; fax: +1-905-
522-9033.
E-mail address: andrewsd@mcmaster.ca (D.W. Andrews).
www.bba-direct.com
Biochimica et Biophysica Acta 1644 (2004) 115– 123