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doi: 10.1242/10.1242/jcs.00651

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Intramembrane proteolysis by presenilin and presenilin-like proteases

Weiming Xia and Michael S. Wolfe

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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  		Fig. 1. Signal peptide peptidase is a presenilin-like aspartyl protease. Human SPP has seven TM domains with the N-terminus facing the ER lumen and the C-terminus facing the cytoplasm. The active site motif YD is located in the center of TM domain 4, and the corresponding active site motif LGXGD is located in the center of adjacent TM domain 5. Human PS has eight TM domains with both N- and C-termini facing the cytoplasm. The corresponding active motifs are located in the center of TM domains 6 and 7 with reverse orientation. PS and SPP are involved in intramembrane proteolysis of type I and II substrates, respectively. Conserved PALL (SPP) and PALP (PS) motifs in the C-terminus are also shown.

 


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  		Fig. 2. Type I membrane proteins as substrates for PS-mediated {gamma}-secretase cleavage. APP, Notch, ErbB-4, E-cadherin, CD44, LRP and nectin1{alpha} are type I membrane proteins. APP, Notch and CD44 can be cleaved at the middle of TM domains and at a residue close to the interface of membrane and cytoplasm (red arrows). Cleavage of ErbB-4 occurs at several residues from the membrane-cytoplasm boundary, and cleavage of E-cadherin occurs right at the interface. LRP and nectin 1{alpha} undergo proteolysis in the TM domain to release the intracellular domain. Ectodomain shedding of FL membrane proteins (blue arrow) is required for subsequent intramembrane proteolysis mediated by PS.

 

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