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Review
. 2009 May 22;284(21):13969-73.
doi: 10.1074/jbc.R800039200. Epub 2009 Feb 3.

Intramembrane-cleaving proteases

Michael S Wolfe  1
Affiliations
Review

Intramembrane-cleaving proteases

Michael S Wolfe. J Biol Chem. .
No abstract available

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Figures

FIGURE 1.
FIGURE 1.
Intramembrane metalloproteases. A, S2P contains conserved metalloprotease HEXXH and LDG motifs. SREBP is first cleaved by S1P in the luminal loop. The regulatory domain (Reg) helps to ensure that S1P proteolysis occurs when cholesterol levels are low. Subsequent intramembrane proteolysis releases this transcription factor for expression of genes essential to cholesterol and fatty acid synthesis. B, crystal structure of an archaeal S2P in the closed conformation. Zinc (gray sphere) is proximal to two histidines in TMD2, one aspartate in the kinked TMD4 (side chain sticks), and one glutamate in TMD2 (not shown). In the open conformation, TMD1 and TMD6 are considerably farther apart, suggesting the site of lateral gating by which substrate TMD accesses the internal active site.
FIGURE 2.
FIGURE 2.
Intramembrane aspartyl proteases. A, PS, the γ-secretase complex, and the proteolysis of APP. PS is cut into two pieces, an NTF (dark portion) and a CTF (light portion), that remain associated. Each fragment donates one aspartate essential for γ-secretase activity. APP is first cleaved in the extracellular domain by β-secretase, and the remnant is cleaved twice within the membrane by γ-secretase to produce the Aβ peptide of Alzheimer disease (secreted) and the intracellular domain (freed into the cytosol). Inset, PS interacts with three other membrane proteins, nicastrin (NCT), Aph-1, and Pen-2, to form active γ-secretase. B, SPP. Signal peptides are removed from membrane proteins via signal peptidase (SP), and these peptides are released from the membrane by SPP-mediated intramembrane proteolysis. Like PS, SPP contains two aspartates essential for protease activity, but the conserved aspartate-containing motifs are in the opposite orientation compared with their PS counterparts.
FIGURE 3.
FIGURE 3.
Intramembrane serine proteases. A, Rhomboid proteins contain a conserved serine and histidine, which compose the catalytic dyad of a serine protease. Rhomboid-1 cleaves within the transmembrane region of the Drosophila EGF-like growth factor Spitz. B, structure of E. coli Rhomboid GlpG. The serine in TMD4 and the histidine in TMD6 are coordinated in a manner consistent with known serine proteases and at a depth within the membrane consistent with the site of proteolysis of Rhomboid substrates.
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References

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