Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA (e-mail: wxia{at}rics.bwh.harvard.edu; mwolfe{at}rics.bwh.harvard.edu)
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Summary |
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Key words: Presenilin, Secretase, Signal peptide peptidase, Amyloid, Alzheimer's disease
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Introduction |
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The production of Aß from APP involves sequential proteolysis by
ß- and -secretases. Cleavage by
-secretase is heterogeneous
and generates C-terminal variations in Aß. Because FAD mutations in PS
increase Aß42 levels in particular, PS must affect the
selectivity of
-secretase. Deletion of PS1 in mice is lethal, producing
a major disruption of somite segmentation
(Shen et al., 1997
;
Wong et al., 1997
).
Neurogenesis is impaired, and massive neuronal loss is observed in specific
regions (Shen et al., 1997
).
The developmental abnormalities and embryonic lethality can be rescued by both
wild-type and FAD-mutant PS1 (Davis et al.,
1998
; Qian et al.,
1998
), which indicates that disease-causing PS mutants are at
least partially functional. Cleavage of APP by
-secretase in cultured
PS1-knockout neurons is markedly inhibited
(De Strooper et al., 1998
;
Herreman et al., 2000
;
Zhang et al., 2000
), and
PS-/- PS2-/- neurons produce undetectable levels of
secreted Aß. This clearly demonstrates that PS is required for
-secretase activity and Aß generation.
Studies with inhibitors have shown that -secretase has
characteristics of an aspartyl protease
(Shearman et al., 2000
;
Wolfe et al., 1999a
).
Identification of two conserved aspartate residues in transmembrane (TM)
domains 6 and 7 of PS critical for
-secretase activity (D257 and D385
in PS1) provided the conceptual basis for the novel hypothesis that PS is the
aspartyl
-secretase (Wolfe et al.,
1999b
). When either aspartate residue in PS1
(Wolfe et al., 1999b
) or PS2
(Kimberly et al., 2000
;
Steiner et al., 1999
) is
mutated,
-secretase activity is blocked, and Aß levels are
significantly reduced in cultured cells. This was also observed in transgenic
mice overexpressing aspartate D257A mutant PS1
(Xia et al., 2001
). Further
evidence summarized below suggests that not only is PS an aspartyl protease
but an entire class of PS-like proteases is involved in intramembrane
proteolysis of both type I and II membrane proteins.
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PS: the active site of ![]() |
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Besides endoproteolysis of PS to form functional NTF-CTF, its association
with other components is apparently also critical for -secretase
activity. Investigation of the PS-containing high-molecular-weight (HMW)
complex indicates that additional cofactors intimately associate with PS to
form the active
-secretase complex. Nicastrin, which was initially
identified from PS1 co-immunoprecipitates
(Yu et al., 2000
), binds
specifically to an immobilized transition state analogue
-secretase
inhibitor (Esler et al.,
2002
). Nicastrin and PS1 NTF-CTF are capable of binding to this
immobilized
-secretase inhibitor under conditions that also maintain
the
-secretase activity; conditions disrupting the association of these
proteins with the inhibitor also render the complex inactive. In common with
anti-PS1 antibodies, anti-nicastrin antibodies can precipitate the functional
-secretase complex (Esler et al.,
2002
). Although glycosylation of nicastrin is not absolutely
required for
-secretase activity
(Herreman et al., 2003
),
mainly the mature form of nicastrin was identified in the HMW
-secretase complex, and levels of nicastrin in cells closely correlate
with PS levels (Arawaka et al.,
2002
; Kimberly et al.,
2002
; Leem et al.,
2002
; Tomita et al.,
2002
; Yang et al.,
2002
). Reduction of PS levels leads to a concomitant reduction in
nicastrin levels, and downregulation of nicastrin expression decreases the
levels of stabilized PS molecules. Thus, reduction in the amount of either
protein decreases Aß generation
(Edbauer et al., 2002
).
Presenilin is not only involved in the intramembranous processing of APP
but also in the processing of and signaling from the Notch receptor
(Kopan and Goate, 2002).
Proper Notch signaling is critical to a wide variety of cell fate
determinations during embryonic development and adulthood. Notch is a type I
integral membrane protein that has a large extracellular domain, a single
transmembrane domain and an intracellular domain. After translation, the
receptor is proteolyzed in the trans-Golgi as part of its maturation into a
heterodimeric cell surface receptor. Notch then suffers a second proteolysis
as a result of ligand activation, leading to shedding of the extracellular
domain of the receptor. The remaining membrane-bound C-terminal stub is
subsequently cleaved within its transmembrane domain to release the Notch
intracellular domain, which translocates to the nucleus where it regulates
gene expression. This final intramembrane proteolysis is mediated by the
multi-component
-secretase complex
(Fortini, 2002
).
Genetic screening for proteins that cause Notch-like defects and
interact with presenilin and nicastrin orthologues in C. elegans
(SEL-12 and APH-2, respectively) identified two multipass transmembrane
proteins: APH-1 (anterior pharynx defective) and PEN-2 (presenilin enhancer)
(Francis et al., 2002;
Goutte et al., 2002
). C.
elegans APH-1 and its human orthologues are predicted to contain seven
membrane-spanning regions, and they are closely associated with SEL-12/PS and
APH-2/nicastrin in C. elegans/humans. APH-1 apparently facilitates
the localization of APH-2 to the cell surface of C. elegans embryos:
most APH-2 remains in ER-like compartments close to the nucleus in APH-1
mutant embryos (Goutte et al.,
2002
). The phenotype of APH-1-mutant embryos is similar to that of
embryos possessing defective SEL-12, indicating that APH-1 and SEL-12 (PS) may
act together for the proper function of APH-2 (nicastrin)
(Goutte et al., 2002
).
Further genetic screening for Notch pathway components in C.
elegans not only confirmed APH-1 as a regulator of -secretase but
also revealed the additional component PEN-2
(Francis et al., 2002
). PEN-2
has two predicted TM domains. It does not contain any known protease motif and
does not carry a signal peptide. Interestingly, its chromosomal location
(chromosome 19) is close to the ApoE gene. The
ApoE
4 allele is the major risk factor associated with
AD. Inactivation of APH-1 or PEN-2 in cultured Drosophila cells
significantly reduces the
-secretase cleavage of APP and Notch, and PS
NTF-CTF levels are also reduced (Francis
et al., 2002
). In mammalian cells, PEN-2 protein levels are
significantly reduced in the absence of PS; downregulation of nicastrin
synthesis similarly causes a reduction in PEN-2 levels. Downregulation of
PEN-2 synthesis likewise decreases the levels of stabilized PS molecules and
mature nicastrin, with a concomitant reduction in
-secretase activity
(Steiner et al., 2002
).
Reduction of APH-1 levels in mammalian cells also reduces
-secretase
activity (Lee et al., 2002b
).
Recent studies have demonstrated that APH-1, PEN-2 and nicastrin directly
associate with PS (Gu et al.,
2003
; Luo et al.,
2003
; Kimberly et al.,
2003
) and overexpression of these four proteins enhances
-secretase activity (Edbauer et
al., 2003
; Kimberly et al.,
2003
; Takasugi et al.,
2003
). Increased levels of APH-1, PEN-2 and PS1 facilitate PS
heterodimer formation, as well as glycosylation of nicastrin
(Edbauer et al., 2003
;
Kimberly et al., 2003
;
Takasugi et al., 2003
). Thus,
nicastrin, APH-1 and PEN-2 regulate one another and are indispensable for
-secretase activity. Although reconstitution of PS, nicastrin, APH-1
and PEN-2 in yeast leads to PS endoproteolysis and Aß/AICD production
(Edbauer et al., 2003
),
definitive evidence for PS as a protease requires in vitro reconstitution
assays using purified PS and substrate.
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From bacterial proteases to PS: a conserved active site motif |
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PS homologues with putative protease activity |
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Rogaev and colleagues independently found the same group of PS-like
proteins, which they collectively name IMPAS (for
intramembrane-protease-associated activity) or IMPs
(Grigorenko et al., 2002). For
example, IMP1 is identical to PSH3, which is encoded by a gene located on
chromosome 20. Furthermore, the sequence of IMP1/PSH3 is identical to that of
signal peptide peptidase (SPP), the protease involved in cleaving signal
peptide remnants (Grigorenko et al.,
2002
; Ponting et al.,
2002
; Weihofen et al.,
2002
) (see below).
![]() |
Signal peptide peptidase: PS-like aspartyl protease |
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|
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Substrates: type I and II membrane proteins |
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|
Studies of SPP substrates (signal peptides) indicate that the valine
residue close to the interface between membrane and cytoplasm is not required
for cleavage (Lemberg and Martoglio,
2002). Although SPP can cleave signal peptides from the hormone
prolactin, human polymorphic MHC class I molecules, calreticulin, and the
viral proteins vesicular stomatitis virus G protein (VSVG), it fails to cleave
signal peptides from human cytomegalovirus glycoprotein UL40 and RNase A.
Sequence comparison of these substrates suggests that residues having a
tendency to disrupt the helix of the TM domain are required for SPP cleavage.
Importantly, signal peptidase cleavage of pre-proteins to form a signal
peptide is a prerequisite for SPP cleavage, which is consistent with the
requirement for ectodomain shedding in
-secretase substrates. Both type
I and II membrane proteins thus undergo ectodomain shedding as a prerequisite
for
-secretase/PS- or SPP-mediated intramembrane proteolysis.
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Conclusion |
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Acknowledgments |
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References |
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