Psychiatry related information on PSENEN

• PEN-2 is an integral membrane protein that is a necessary component of the gamma-secretase complex, which is central in the pathogenesis of Alzheimer's disease and is also required for Notch signaling [1].

High impact information on PSENEN

• Depletion of PEN-2 by RNA interference prevents endoproteolysis of presenilin and promotes stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons [2].
• Only recently it has become clear that a protease complex containing presenilin, nicastrin, PEN-2 and probably APH-1 provides the long sought gamma-secretase activity [3].
• Despite the fact that PEN-2 is known to mediate endoproteolytic cleavage of full-length PS and APH-1 and nicastrin are required for maintaining the stability of the complex, the detailed physiological function of each component remain elusive [4].
• Activation of the CREB transcriptional factor by forskolin dramatically promoted the expression of PEN-2 mRNA and protein, whereas the other components of the gamma-secretase complex remained unaffected [4].
• Further analysis revealed a CREB binding site located in the 238-bp region that is essential for the transcriptional activity of the PEN-2 promoter [4].

Biological context of PSENEN

• Stabilization of the resultant N- and C-terminal fragments, which carry the catalytically active site aspartates, but not endoproteolysis itself, requires the C-terminal domain of PEN-2 [5].
• Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed the binding of CREB to the PEN-2 promoter region both in vitro and in vivo [4].
• Similarly, PEN-2 levels are reduced upon RNA interference-mediated down-regulation of Nct [6].
• We found that the N-linked glycosylation sites present in the N- and C-terminal domains of PEN-2 were utilized, whereas a site in the hydrophilic "loop" region connecting the two transmembrane domains was not [1].
• These studies suggest that: 1) both the presence and amino acid sequence of the conserved DYLSF domain at the C terminus of PEN-2 (residues 90-94) is critical for binding PEN-2 to other components in the presenilin complex and 2) the overall length of the exposed C terminus is critical for functional gamma-secretase activity [7].

Anatomical context of PSENEN

• Biophysical and genetic studies indicate that presenilin-1, which contains the proteolytic active site, and three other membrane proteins [nicastrin, anterior pharynx defective-1 (APH-1), and presenilin enhancer-2 (PEN-2)] are required to form the core of the active gamma-secretase complex [8].
• Thus, PEN-2 spans the membrane twice, with the N and C termini facing the lumen of the endoplasmic reticulum [1].
• Immunofluorescence microscopy with selective permeabilization of the plasma membrane of cells expressing epitope-tagged forms of PEN-2 confirmed the lumenal location of both the N and C termini [1].
• In N2a and 293 cell lines that stably overexpress PS1, APH-1, NCT, and PEN-2, PS1 fragment levels are elevated by up to 10-fold over endogenous levels [9].
• Three distinct classes of penaeidins, named PEN2, PEN3, and PEN4, are expressed in the hemocytes of the Pacific white shrimp, Litopenaeus vannamei [10].

Associations of PSENEN with chemical compounds

• Interestingly, only simultaneous, but not individual substitution of the highly conserved D90, F94, P97 and G99 residues with alanine interfered with PEN-2 function [5].
• After injection of LPS, mRNA levels of antimicrobial peptides, penaeidin 2 (PEN2), penaeidin 3 (PEN3), penaeidin 4 (PEN4) and crustin decreased in a dose-dependent manner, while mRNA levels of serine proteinase and proPO did not change significantly [11].
• For DPDPE, however, this was only possible with a positive dihedral angle for the disulfide bond due to the presence of the beta-carbon methyls of Pen2 [12].

Physical interactions of PSENEN

• Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2 [13].

Other interactions of PSENEN

• Taken together, our data suggest that the PS-subunit stabilizing function of PEN-2 depends on length and overall sequence of its C-terminal domain [5].
• APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity [14].
• Direct binding of unassembled Pen2 to Rer1 is mediated by the first transmembrane domain of Pen2, and a conserved asparagine in this domain is required [15].

References