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Contribution of the Presenilins in the cell biology, structure and function of γ-secretase.
Seminars in Cell & Developmental Biology ( IF 7.3 ) Pub Date : 2020-03-04 , DOI: 10.1016/j.semcdb.2020.02.005
Abril Escamilla-Ayala 1 , Rosanne Wouters 1 , Ragna Sannerud 1 , Wim Annaert 1
Affiliation  

γ-Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer’s disease. Therefore, understanding the regulation of its activity is of major importance to improve drug design and develop novel therapeutics. γ-Secretase belongs to the family of intramembrane cleaving proteases (i-CLiPs), which cleaves its substrates in a process termed regulated intramembrane proteolysis (RIP). During RIP, type-I transmembrane proteins are first cleaved within their ectodomain by a sheddase and then within their transmembrane domain by γ-secretase. γ-Secretase is composed of four integral membrane proteins that are all essential for its function: presenilin (PSEN), anterior pharynx defective 1 (APH1), nicastrin (NCT) and presenilin enhancer 2 (PEN-2). Given the presence of two PSEN homologues (PSEN1 & 2) and several APH1 isoforms, a heterogeneity exists in cellular γ-secretase complexes. It is becoming clear that each of these complexes has overlapping as well as distinct biological characteristics. This review summarizes our current knowledge on complex formation, trafficking, subcellular localization, interactors and the structure of γ-secretase, with a focus, when possible or known, on the contribution of PSEN1 and PSEN2 herein.



中文翻译:

早老蛋白在γ-分泌酶的细胞生物学,结构和功能中的贡献。

γ-分泌酶裂解对于许多生物学过程都是必不可少的,并且其失调与疾病相关,包括癌症和阿尔茨海默氏病。因此,了解其活性的调节对于改善药物设计和开发新的疗法至关重要。γ-分泌酶属于膜内切割蛋白酶(i-CLiPs)家族,其在称为调节膜内蛋白水解(RIP)的过程中切割其底物。在RIP期间,I型跨膜蛋白首先在其胞外域中被一个sheddase裂解,然后在其跨膜域中被γ-分泌酶裂解。γ-分泌酶由四个完整的膜蛋白组成,这些蛋白均对其功能至关重要:早老素(PSEN),前咽缺陷1(APH1),尼卡斯汀(NCT)和早老素增强剂2(PEN-2)。考虑到存在两个PSEN同源物(PSEN1和2)和几个APH1同工型,细胞γ-分泌酶复合物中存在异质性。显然,这些复合物中的每一种都具有重叠以及独特的生物学特性。这篇综述总结了我们对复合物形成,运输,亚细胞定位,相互作用子和γ-分泌酶结构的当前知识,在可能或已知的情况下,重点关注本文中PSEN1和PSEN2的贡献。

更新日期:2020-03-04
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