Presenilin-1

Definition:

Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the presence of the other members of the gamma-secretase complex for protease activity. Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin). Under conditions of apoptosis or calcium influx, cleaves CDH1. This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling. Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).

References:

[1]. Dieter Edbauer, et al. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003 May;5(5):486-8. [Content Brief]

[2]. Xiao-Chen Bai, et al. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-217. [Content Brief]

[3]. Peilong Lu, et al. Three-dimensional structure of human γ-secretase. Nature. 2014 Aug 14;512(7513):166-170. [Content Brief]

[4]. M Murayama, et al. Direct association of presenilin-1 with beta-catenin. FEBS Lett. 1998 Aug 14;433(1-2):73-7. [Content Brief]

[5]. Guanghui Yang, et al. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. [Content Brief]

[6]. Rui Zhou, et al. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428):eaaw0930. [Content Brief]

[7]. Patrick C Fraering, et al. Purification and characterization of the human gamma-secretase complex. Biochemistry. 2004 Aug 3;43(30):9774-89. [Content Brief]

[8]. W J Ray, et al. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999 Dec 17;274(51):36801-7. [Content Brief]

[9]. Jun Wang, et al. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J Neurochem. 2006 Jan;96(1):218-27. [Content Brief]

[10]. Huiping Tu, et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell. 2006 Sep 8;126(5):981-93. [Content Brief]

[11]. H Steiner, et al. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry. 1999 Nov 2;38(44):14600-5. [Content Brief]

[12]. L Kulic, et al. Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. [Content Brief]

[13]. M S Wolfe, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 Apr 8;398(6727):513-7. [Content Brief]

[14]. W Taylor Kimberly, et al. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6382-7. [Content Brief]

[15]. Claudia Litterst, et al. Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem. 2007 Jun 1;282(22):16155-63. [Content Brief]

[16]. Wei-Ting Chen, et al. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation. Mol Neurobiol. 2015 Dec;52(3):1835-1849. [Content Brief]

[17]. Philippe Marambaud, et al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002 Apr 15;21(8):1948-56. [Content Brief]

[18]. Jonathan D J Wrigley, et al. Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding. J Neurochem. 2004 Sep;90(6):1312-20. [Content Brief]

[19]. Jing Dong, et al. A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. J Alzheimers Dis. 2017;57(2):613-623. [Content Brief]

[20]. Elizabeth A Heilig, et al. A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. [Content Brief]

[21]. O Berezovska, et al. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J Neurochem. 2000 Aug;75(2):583-93. [Content Brief]

[22]. Wieslaw K Dowjat, et al. A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. J Alzheimers Dis. 2004 Feb;6(1):31-43. [Content Brief]

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