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Review
. 2013 Dec;1828(12):2886-97.
doi: 10.1016/j.bbamem.2013.04.015.

Toward the structure of presenilin/γ-secretase and presenilin homologs

Michael S Wolfe  1
Affiliations
Review

Toward the structure of presenilin/γ-secretase and presenilin homologs

Michael S Wolfe. Biochim Biophys Acta. 2013 Dec.

Abstract

Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembrane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein-protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.

Keywords: AICD; APP; APP intracellular domain; Alzheimer's disease; Aβ; C-terminal fragment; CTF; Membrane; Methanoculleus marisnigri JR1 presenilin homolog; N-terminal fragment; NTF; PS1; PSH; Protease; S2P; SPP; Signal peptide peptidase; TMD; amyloid β-protein; amyloid β-protein precursor; i-CLiP; intramembrane-cleaving protease; mmPSH; presenilin homolog; presenilin-1; signal peptide peptidase; site 2 protease; transmembrane domain.

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Figures

Fig. 1
Fig. 1
Membrane topology of presenilins and APP and sites of proteolysis. Presenilin has nine transmembrane domains and two conserved aspartates, in TMD 6 and TMD 7. Upon assembly with other members of the γ-secretase complex, presenilin undergoes autoproteolysis within the large loop connecting TMD 6 and TMD 7 to form an N-terminal fragment (NTF, copper) and C-terminal fragment (CTF, gold). Each presenilin subunit contributes an aspartate to the active site. APP is a type I integral membrane protein that undergoes ectodomain shedding by β-secretase, with retention of a C-terminal fragment in the membrane that is subsequently cleaved by γ-secretase in at least two sites: a γ site to release the Aβ peptide to the lumenal/extracellular space and an ε site to release the APP intracellular domain (AICD) into the cytosol.
Fig. 2
Fig. 2
Membrane topology of signal peptide peptidase (SPP) and its substrates. SPP, like presenilins, has nine transmembrane domains, with TMD 6 and TMD 7 contributing the active site aspartates. However, the membrane orientation of SPP is opposite that of presenilins. The membrane orientation of SPP substrates is likewise opposite that of presenilin substrates: the signal peptide of type I integral membrane proteins, released by signal peptidase (SP), runs from cytosol to lumenal/extracellular space going from N- to C-terminus.
Fig. 3
Fig. 3
Membrane topology of the other three components of γ-secretase: nicastrin, Aph-1 and Pen-2.
Fig. 4
Fig. 4
Model for subunit interaction within the γ-secretase complex and substrate interaction. Presenilin NTF (copper), presenilin CTF (gold), Pen-2 (red), Aph-1 (blue), and nicastrin (green). Substrate APP CTF (yellow) is shown interacting at the interface between presenilin NTF and CTF via its transmembrane domain and with nicastrin via its N-terminus. Substrate then enters the internal active site (pink star) for proteolysis to Aβ and AICD.
Fig. 5
Fig. 5
Structure of the γ-secretase complex at 12 Å resolution as determined by cryo-electron microscopy. Coloration represents different domains of the complex and is not meant to imply specific subunits. However, the large nicastrin ectodomain, identified with lectin, is located on the lumenal/extracellular side. The thick red curved line in panel A identifies a groove on the outside of the membrane-spanning surface that may be the site of initial substrate binding. The structure reveals three openings, seen in the cutaway view in panel B, by which catalytic water may gain access to the active site.
Fig. 6
Fig. 6
Crystal structure of the archaeal presenilin homolog mmPSH. Cartoon representation, viewed looking perpendicular to the membrane, allows visualization of the arrangement of the nine transmembrane domains. The side chains of the conserved aspartates in TMD 6 and TMD 7, forming the active site, are shown as sticks. A hole that traverses the entire membrane is formed by TMDs 2, 3, 5 and 7. Two potential routes of substrate access to the active site are also denoted. Rendered from RCSB PDB 4HYG.
Fig. 7
Fig. 7
Mapping of sites of Alzheimer-causing presenilin mutations onto the space-filled structure of mmPSH. Corresponding sites in mmPSH are colored according to transmembrane domain: TMD 1 (dark red), TMD 2 (orange), TMD 3 (pink), TMD 4 (brick red), TMD 5 (magenta), TMD 6 (light brown), TMD 7 (dark brown), TMD 8 (olive), and TMD 9 (pale yellow). (A) The active site is lined with sites of mutation. The catalytic aspartates are colored according to atom (carbon: green, oxygen: red). (B) The membrane hole is likewise lined with sites of mutations. (C) Sites of mutations in TMD 1 run the length of one side of the helix facing the membrane and may together correspond to a site of protein–protein interaction in the γ-secretase complex. Rendered from RCSB PDB 4HYG.
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