Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative
Discussion of GXGD-type Aspartyl
Proteases |
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Authors: | Regina Fluhrer Harald Steiner and Christian Haass |
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Institution: | Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and Adolf Butenandt Institute, Biochemistry, Ludwig-Maximilians University, Munich, 80336 Munich, Germany |
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Abstract: | Intramembrane-cleaving proteases are required for reverse signaling and
membrane protein degradation. A major class of these proteases is represented
by the GXGD-type aspartyl proteases. GXGD describes a novel
signature sequence that distinguishes these proteases from conventional
aspartyl proteases. Members of the family of the GXGD-type aspartyl
proteases are the Alzheimer disease-related γ-secretase, the signal
peptide peptidases and their homologs, and the bacterial type IV prepilin
peptidases. We will describe the major biochemical and functional properties
of the signal peptide peptidases and their relatives. We then compare these
properties with those of γ-secretase and discuss common mechanisms but
also point out a number of substantial differences.During the last years, a number of intramembrane-cleaving proteases termed
I-CLiPs3 have been
identified (1). I-CLiPs are
generally involved in regulated intramembrane proteolysis
(2). Upon shedding of a large
part of the ectodomain of membrane proteins, the remaining membrane-retained
stub is cleaved by specialized proteases within the hydrophobic lipid
membrane. Generally, this cleavage can have two predominant biological
functions: first, signaling via the liberated ICD within the
substrate-expressing cell (reverse signaling)
(2); and second, degradation of
membrane-retained stubs, which are not required for any further biological
function (3). I-CLiPs of three
protease classes, metalloproteases, serine proteases, and aspartyl proteases,
have been discovered so far (see accompanying minireview by Wolfe
(44)).Intramembrane-cleaving aspartyl proteases are represented by the class of
the GXGD-type proteases
(4). These are unconventional
aspartyl proteases that, like the conventional aspartyl proteases, utilize two
critical aspartyl residues for peptide bond cleavage. However, in contrast to
the conventional proteases, the critical aspartyl residues are located within
two TMDs ().
Moreover, these aspartyl residues are embedded in active-site motifs that are
completely different from those of conventional aspartyl proteases. The class
of GXGD-type aspartyl proteases is currently represented by three
different protease families, the most prominent of which is the PS family,
providing the catalytically active subunit of γ-secretase
()
(4). PS/γ-secretase is
the I-CLiP that liberates amyloid β-peptide, the major component of
senile plaques in Alzheimer disease patients
(5). In addition, the bacterial
type IV prepilin peptidases also belong to the class of the GXGD-type
proteases (6). Besides these
two protease families, two additional subfamilies of related proteases that
also belong to the GXGD-type aspartyl protease family have been
identified. These include SPP as well as the SPP homologs, the
SPP-like (SPPL) proteases
()
(7,
8).Open in a separate windowA, schematic representation of SPPL2a/b, a member of the SPP/SPPL
family, and PS, the catalytic core of theγ-secretase. Note the opposite
topology of the active sites (indicated by arrows) of the two
proteases and their substrates, APP for PS and TNFα for SPPL2a/b.
B, proteolytic processing of APP and TNFα. Shedding releases
the extracellular part of APP (APPs) and TNFα
(TNFα soluble). In the case of APP, a C-terminal
fragment (APP CTF), and in case of TNFα, an N-terminal fragment
(TNFα NTF) are produced. These membrane-bound
fragments are substrate to intramembrane cleavage by PS or SPPL2a/b,
respectively, releasing small peptides to the extracellular space
(Aβ and TNFα C-domain, respectively) and
to the cytosol (APP intracellular domain (AICD) and
TNFα ICD), respectively). TNFα
FL, full-length TNFα.We will first describe the biochemical, functional, and structural
properties of SPP family members. By comparison of these properties, we will
then identify common mechanisms of intramembrane proteolysis by
GXGD-type proteases but also point out some fundamental
differences. |
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