Suppr超能文献

早老素复合物的结构和化学生物学。

Structural and Chemical Biology of Presenilin Complexes.

机构信息

Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139.

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.

出版信息

Cold Spring Harb Perspect Med. 2017 Dec 1;7(12):a024067. doi: 10.1101/cshperspect.a024067.

Abstract

The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.

摘要

早老素蛋白是包含早老素 1 或 2、前咽缺陷蛋白 1(APH1)、尼卡斯特林和 PEN-2 的四聚体复合物的催化亚基。其他成分,如 TMP21,可能存在于一些特殊的复合物中。早老素复合物是一种独特的天冬氨酸蛋白酶家族的创始成员,它催化 I 型跨膜蛋白(包括淀粉样前体蛋白(APP)和 Notch)的跨膜结构域的 γ、ɛ、ζ 位点切割。在这里,我们详细介绍了这种不寻常酶的结构和化学生物学。综上所述,这些研究表明,该复合物存在于几种构象中,复合物构象的细微远程(变构)变化为底物进入催化位点以及变构抑制剂和调节剂的作用机制提供了支持。了解这些变化的力学机制将有助于设计 γ-分泌酶调节剂(GSM)化合物,这些化合物可以调节 γ、ɛ、ζ 位点切割的相对效率和/或底物特异性。

相似文献

1
Structural and Chemical Biology of Presenilin Complexes.
Cold Spring Harb Perspect Med. 2017 Dec 1;7(12):a024067. doi: 10.1101/cshperspect.a024067.
2
Toward the structure of presenilin/γ-secretase and presenilin homologs.
Biochim Biophys Acta. 2013 Dec;1828(12):2886-97. doi: 10.1016/j.bbamem.2013.04.015.
3
Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.
Int J Mol Sci. 2021 Dec 18;22(24):13600. doi: 10.3390/ijms222413600.
5
Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing.
J Alzheimers Dis. 2017;56(4):1263-1269. doi: 10.3233/JAD-161094.
7
Structural biology of presenilin 1 complexes.
Mol Neurodegener. 2014 Dec 18;9:59. doi: 10.1186/1750-1326-9-59.
8
Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes.
Biochemistry. 2011 Jun 7;50(22):4973-80. doi: 10.1021/bi200026m. Epub 2011 May 13.
9
Assembly of the presenilin γ-/ε-secretase complex.
J Neurochem. 2012 Jan;120 Suppl 1:84-88. doi: 10.1111/j.1471-4159.2011.07505.x. Epub 2011 Nov 28.
10
Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the γ-secretase complex.
J Biol Chem. 2015 Mar 13;290(11):7169-84. doi: 10.1074/jbc.M114.601286. Epub 2015 Jan 22.

引用本文的文献

2
Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease.
Neuron. 2023 Oct 18;111(20):3176-3194.e7. doi: 10.1016/j.neuron.2023.07.005. Epub 2023 Aug 4.
3
Relationship Between Amyloid-β Deposition and Blood-Brain Barrier Dysfunction in Alzheimer's Disease.
Front Cell Neurosci. 2021 Jul 19;15:695479. doi: 10.3389/fncel.2021.695479. eCollection 2021.
5
Contextual Regulation of Skeletal Physiology by Notch Signaling.
Curr Osteoporos Rep. 2019 Aug;17(4):217-225. doi: 10.1007/s11914-019-00516-y.
6
Antibody Therapeutics Targeting Aβ and Tau.
Cold Spring Harb Perspect Med. 2017 Oct 3;7(10):a024331. doi: 10.1101/cshperspect.a024331.
7
Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease.
Cold Spring Harb Perspect Med. 2017 Jun 1;7(6):a024539. doi: 10.1101/cshperspect.a024539.

本文引用的文献

1
Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.
Cell. 2016 Jun 30;166(1):193-208. doi: 10.1016/j.cell.2016.05.020. Epub 2016 Jun 9.
2
4
An atomic structure of human γ-secretase.
Nature. 2015 Sep 10;525(7568):212-217. doi: 10.1038/nature14892. Epub 2015 Aug 17.
5
Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.
Mol Psychiatry. 2015 Oct;20(10):1179-87. doi: 10.1038/mp.2015.74. Epub 2015 Jun 9.
6
Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.
ACS Med Chem Lett. 2015 Apr 3;6(5):596-601. doi: 10.1021/acsmedchemlett.5b00070. eCollection 2015 May 14.
7
Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease.
Neuron. 2015 Mar 4;85(5):967-81. doi: 10.1016/j.neuron.2015.02.010.
8
Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.
Bioorg Med Chem Lett. 2015 Apr 1;25(7):1621-6. doi: 10.1016/j.bmcl.2015.01.051. Epub 2015 Feb 10.
9
The dynamic conformational landscape of gamma-secretase.
J Cell Sci. 2015 Feb 1;128(3):589-98. doi: 10.1242/jcs.164384.
10
Lessons from a failed γ-secretase Alzheimer trial.
Cell. 2014 Nov 6;159(4):721-6. doi: 10.1016/j.cell.2014.10.016.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验