Presenilin endoproteolysis is an intramolecular cleavage

Brunkan, Anne L.; Martínez, Maribel; Walker, Emily; Goate, Alison M.

doi:10.1016/j.mcn.2004.12.012

Cited by 31 publications

(39 citation statements)

References 68 publications

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“…␥-Secretase substrates sit in the active site of ␥-secretase, with their N termini toward the extracellular space (24,29). However, ␥-secretase also cleaves itself autocatalytically within the hydrophobic domain VII (HDVII) of PS in the large intracellular loop (11,13). Therefore, HDVII must adopt a similar topology to substrates and in fact is the first substrate of ␥-secretase.…”

Section: Discussionmentioning

confidence: 99%

“…The formation of the ␥-secretase complex is tightly controlled, with an ordered assembly of subunits coupled to spatial restriction (10). It is believed that the last step of the complicated ␥-secretase maturation and activation process involves in cis endoproteolysis of the PS holoprotein (11)(12)(13). It is this form of ␥-secretase with PS in its N-and C-terminal fragments (NTF and CTF, respectively) that represents the fully mature, proteolytically active enzyme.…”

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confidence: 99%

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Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity

Dries

Shah

Han

et al. 2009

Journal of Biological Chemistry

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␥-Secretase is a proteolytic membrane complex that processes a variety of substrates including the amyloid precursor protein and the Notch receptor. Earlier we showed that one of the components of this complex, nicastrin (NCT), functions as a receptor for ␥-secretase substrates. A recent report challenged this, arguing instead that the Glu-333 residue of NCT predicted to participate in substrate recognition only participates in ␥-secretase complex maturation and not in activity per se. Here, we present evidence that Glu-333 directly participates in ␥-secretase activity. By normalizing to the active pool of ␥-secretase with two separate methods, we establish that ␥-secretase complexes containing NCT-E333A are indeed deficient in intrinsic activity. We also demonstrate that the NCT-E333A mutant is deficient in its binding to substrates. Moreover, we find that the cleavage of substrates by ␥-secretase activity requires a free N-terminal amine but no minimal length of the extracellular N-terminal stub. Taken together, these studies provide further evidence supporting the role of NCT in substrate recognition. Finally, because ␥-secretase cleaves itself during its maturation and because NCT-E333A also shows defects in ␥-secretase complex maturation, we present a model whereby Glu-333 can serve a dual role via similar mechanisms in the recruitment of both Type 1 membrane proteins for activity and the presenilin intracellular loop during complex maturation.The brains of Alzheimer disease patients are characterized by dense neuritic plaques that consist of the insoluble ␤-amyloid peptide (A␤) 2 and neurons containing neurofibrillary tangles of the Tau protein (1, 2). The A␤ peptide is produced via the sequential proteolysis of APP by ␤-and ␥-secretase (3).␥-secretase is a multisubunit complex consisting of at least four proteins: presenilin (PS), NCT, APH-1, and PEN-2, all of which are necessary and sufficient for activity (4 -9). The formation of the ␥-secretase complex is tightly controlled, with an ordered assembly of subunits coupled to spatial restriction (10). It is believed that the last step of the complicated ␥-secretase maturation and activation process involves in cis endoproteolysis of the PS holoprotein (11-13). It is this form of ␥-secretase with PS in its N-and C-terminal fragments (NTF and CTF, respectively) that represents the fully mature, proteolytically active enzyme.␥-Secretase is a unique protease that cleaves within the lipid bilayer a large number of Type 1 single transmembrane-spanning proteins that vary widely in their sequence and size (14 -16). In a previous report, we demonstrated that NCT functions as a substrate receptor for ␥-secretase (4). In that report, we showed that NCT recruits substrates that have had their large extracellular domains first removed by an upstream protease in a process termed "ectodomain shedding." This process generates a new, short extracellular stub with a free N terminus, which is required for proteolysis by ␥-secretase. We also established that Glu-333 of NCT pa...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity

Dries

Shah

Han

et al. 2009

Journal of Biological Chemistry

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“…PS undergoes endoproteolysis in an intracellular loop between TMD6 and TMD7 to produce the fragments that comprise its active form. 27 The two aspartic acids forming the catalytic site are located in TMD6 and TMD7, and mutation of either one of these aspartic acids renders GS inactive. 13 As for the other components of the GS complex, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 6 it is suggested that Nct is involved in maturation of the complex 28 and binding of the substrate, 29,30 Aph-1 is involved in the assembly and activity of the complex 31,32 and Pen-2 appears to be important for activity, 33 complex stability and trafficking.…”

Section: Gamma Secretase -An Unusual Proteasementioning

confidence: 99%

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

Bursavich¹,

Harrison²,

Blain³

2016

J. Med. Chem.

130

123

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The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain beta amyloid (Aβ) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter non-amyloidogenic Aβ species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as lower cLogP, high central nervous system multiparameter optimization scores, and high sp(3) character.

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“…For example, sel-12 constructs with b-galactosidase insertion after HR 2, -4, -6, -7, -9 10 favor an 8-TM model with the key Asp groups for catalysis on TM VI and VII [400]. Surface epitope labeling on PS1 sites yields variable data with differences in the orientation of Asp groups [395,[403][404][405]. It is unknown whether PS mutations alter binding to c-SC and specificity towards APP/C-99 cleavage [406].…”

Section: Obligatory Components Of C-scmentioning

confidence: 99%

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

Marks

Berg

2009

Neurochem Res

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Secretases are named for enzymes processing amyloid precursor protein (APP), a prototypic type-1 membrane protein. This led directly to discovery of novel Aspartyl proteases (beta-secretases or BACE), a tetramer complex gamma-secretase (gamma-SC) containing presenilins, nicastrin, aph-1 and pen-2, and a new role for metalloprotease(s) of the ADAM family as a alpha-secretases. Recent advances in defining pathways that mediate endosomal-lysosomal-autophagic-exosomal trafficking now provide targets for new drugs to attenuate abnormal production of fibril forming products characteristic of AD. A key to success includes not only characterization of relevant secretases but mechanisms for sorting and transport of key metabolites to abnormal vesicles or sites for assembly of fibrils. New developments we highlight include an important role for an 'early recycling endosome' coated in retromer complex containing lipoprotein receptor LRP-II (SorLA) for switching APP to a non-amyloidogenic pathway for alpha-secretases processing, or to shuttle APP to a 'late endosome compartment' to form Abeta or AICD. LRP11 (SorLA) is of particular importance since it decreases in sporadic AD whose etiology otherwise is unknown.

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Presenilin endoproteolysis is an intramolecular cleavage

Cited by 31 publications

References 68 publications

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity

Glu-333 of Nicastrin Directly Participates in γ-Secretase Activity

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

BACE and γ-Secretase Characterization and Their Sorting as Therapeutic Targets to Reduce Amyloidogenesis

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