Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs.
Recent studies demonstrate that presenilins (PSs) and signal peptide peptidase (SPP) are members of a novel protease family of integral membrane proteins that may utilize a catalytic mechanism similar to classic aspartic proteases such as pepsin, renin and cathepsin D. The defining features of the PSs and SPP are their ability to cleave substrate polypeptides within a transmembrane region, the presence of two active site aspartate residues in adjacent membrane-spanning regions and a conserved PAL motif near their COOH-terminus. PSs appear to be the catalytic subunit of multiprotein complexes that possess gamma-secretase activity. Because this activity generates the amyloid beta peptide (Abeta) deposited in the brain of patients with Alzheimer's disease (AD), PSs are considered therapeutic targets in AD. In contrast to PSs that are not active unless part of a larger complex, SPP does not appear to require protein co-factors. Because of its requirement for hepatitis C virus maturation and a possible immune modulatory role, SPP is also considered a potential therapeutic target. Four additional PS/SPP homologs have been identified in humans; yet, their functions have not been elucidated. Herein, we will review the recent advances in our understanding of the PS/SPP family of proteases as well as discuss aspects of intramembrane cleavage that are not well understood.
Martoglio
Bruno
B
Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland. bruno.martoglio@bc.biol.ethz.ch
Golde
Todd E
TE
D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D020134:Catalytic Domain; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D053764:Presenilin-1; D053766:Presenilin-2; D012697:Serine Endopeptidases / Q000378:metabolism*
D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D016282:Aspartic Acid Endopeptidases