γ-secretase
The presenilin 1 (PS1) and presenilin 2 (PS2) proteins that form the catalytic core of the γ- secretase protease complex were initially discovered in genetic screens for mutations causing early onset forms of familial Alzheimer’s disease (FAD). γ-Secretase is a multi-subunit transmembrane proteolytic complex belonging to the family of intramembrane cleaving proteases (ICliPs) of which there are four classes; the serine proteases of the Rhomboid class, the metalloproteases in the Site-2-proteases (S2P) class and the GXGD aspartyl proteases, signal peptide peptidases (SPP) and γ-secretase. Of all the ICliPs studied to date γ- secretase is unique as it is a four-protein complex, consisting of the presenilins, anterior pharynx-defective 1 (Aph-1), presenilin enhancer 2 (Pen-2) and Nicastrin, which is only found in multicellular organisms.
In humans, two forms of presenilin (PS1 and PS2) and two forms of Aph-1 have been identified, one of the Aph-1 homologs is also expressed in two isoforms via alternative splicing, leading to the possible existence of at least six different γ-secretase complexes that may have tissue- or cell type specificity. To date more than 90 γ-secretase substrates have been identified including APP and a large number of cell surface receptors and adhesion molecules such as Notch, ErbB4, CD44 and E-cadherin. In general substrates that undergo regulated intramembrane proteolysis are initially cleaved in the extracellular domain by sheddases such as TACE (TNFα converting enzyme) or ADAM (a disintegrin and metalloproteinase domain)/α-secretase, or by aspartyl proteases, such as BACE/β-secretase, before cleavage by the I-CLiP family of proteases. Beyond their role in γ-secretase protease complexes, it has been proposed and in some cases demonstrated that the presenilins have many highly conserved γ-secretase independent regulatory functions in cellular processes and cell signalling, including Wnt signalling, endoplasmic reticulum (ER) calcium homeostasis, as well as lysosomal function and autophagy.1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.
References
1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.
In humans, two forms of presenilin (PS1 and PS2) and two forms of Aph-1 have been identified, one of the Aph-1 homologs is also expressed in two isoforms via alternative splicing, leading to the possible existence of at least six different γ-secretase complexes that may have tissue- or cell type specificity. To date more than 90 γ-secretase substrates have been identified including APP and a large number of cell surface receptors and adhesion molecules such as Notch, ErbB4, CD44 and E-cadherin. In general substrates that undergo regulated intramembrane proteolysis are initially cleaved in the extracellular domain by sheddases such as TACE (TNFα converting enzyme) or ADAM (a disintegrin and metalloproteinase domain)/α-secretase, or by aspartyl proteases, such as BACE/β-secretase, before cleavage by the I-CLiP family of proteases. Beyond their role in γ-secretase protease complexes, it has been proposed and in some cases demonstrated that the presenilins have many highly conserved γ-secretase independent regulatory functions in cellular processes and cell signalling, including Wnt signalling, endoplasmic reticulum (ER) calcium homeostasis, as well as lysosomal function and autophagy.1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.
References
1.Duggan SP,et al. Cell Signal. 2016;28(1):1–11.
Wnt/Notch/Hedgehog
γ-secretase
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BMS-433796
产品货号 : M16690
cas no: 935525-13-6
一种有效的口服活性 γ-分泌酶抑制剂,细胞 IC50 为 0.3 nM。 -
E-2012
产品货号 : M16327
cas no: 870843-42-8
一种有效的第二代 γ-分泌酶调节剂,可降低 Aβ(1-39)、Aβ(1-40) 和 A(1-42),并增加 Aβ(1-37)。 -
RO4929097
产品货号 : M16154
cas no: 847925-91-1
RO4929097 (RG 4733) 是一种有效的、选择性的、口服活性的 γ-分泌酶抑制剂,IC50 为 4 nM。 -
MRK-003
产品货号 : M15359
cas no: 623165-93-5
一种有效的 γ-分泌酶抑制剂,IC50 为 0.4 nM,抑制 SH-SY5Y SPA4CT 细胞的 Aβ 分泌。 -
MK-0752
产品货号 : M14568
cas no: 471905-41-6
一种有效的 γ-分泌酶抑制剂,在人 SH-SY5Y 细胞中显示 Aβ40 的剂量依赖性减少,IC50 为 5 nM。