Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype
Intramembrane-cleaving proteases (I-CLiPs) catalyze the hydrolysis of peptide bonds within the transmembrane regions of membrane protein substrates, releasing bioactive fragments that play roles in many physiological and pathological processes. Based on their catalytic mechanism and nucleophile, I-C...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2020.00065/full |
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| author | Xinyue Liu Jing Zhao Yingkai Zhang Iban Ubarretxena-Belandia Iban Ubarretxena-Belandia Scott Forth Scott Forth Raquel L. Lieberman Chunyu Wang Chunyu Wang Chunyu Wang |
| author_facet | Xinyue Liu Jing Zhao Yingkai Zhang Iban Ubarretxena-Belandia Iban Ubarretxena-Belandia Scott Forth Scott Forth Raquel L. Lieberman Chunyu Wang Chunyu Wang Chunyu Wang |
| author_sort | Xinyue Liu |
| collection | DOAJ |
| description | Intramembrane-cleaving proteases (I-CLiPs) catalyze the hydrolysis of peptide bonds within the transmembrane regions of membrane protein substrates, releasing bioactive fragments that play roles in many physiological and pathological processes. Based on their catalytic mechanism and nucleophile, I-CLiPs are classified into metallo, serine, aspartyl, and glutamyl proteases. Presenilin is the most prominent among I-CLiPs, as the catalytic subunit of γ-secretase (GS) complex responsible for cleaving the amyloid precursor protein (APP) and Notch, as well as many other membrane substrates. Recent cryo-electron microscopy (cryo-EM) structures of GS provide new details on how presenilin recognizes and cleaves APP and Notch. First, presenilin transmembrane helix (TM) 2 and 6 are dynamic. Second, upon binding to GS, the substrate TM helix is unwound from the C-terminus, resulting in an intermolecular β-sheet between the substrate and presenilin. The transition of the substrate C-terminus from α-helix to β-sheet is proposed to expose the scissile peptide bond in an extended conformation, leaving it susceptible to protease cleavage. Despite the astounding new insights in recent years, many crucial questions remain unanswered regarding the inner workings of γ-secretase, however. Key unanswered questions include how the enzyme recognizes and recruits substrates, how substrates are translocated from an initial docking site to the active site, how active site aspartates recruit and coordinate catalytic water, and the nature of the mechanisms of processive trimming of the substrate and product release. Answering these questions will have important implications for drug discovery aimed at selectively reducing the amyloid load in Alzheimer’s disease (AD) with minimal side effects. |
| first_indexed | 2024-12-20T19:42:27Z |
| format | Article |
| id | doaj.art-80276726071c49adaf14fdbc590dc305 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-20T19:42:27Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-80276726071c49adaf14fdbc590dc3052022-12-21T19:28:30ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992020-05-011310.3389/fnmol.2020.00065521752Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the PrototypeXinyue Liu0Jing Zhao1Yingkai Zhang2Iban Ubarretxena-Belandia3Iban Ubarretxena-Belandia4Scott Forth5Scott Forth6Raquel L. Lieberman7Chunyu Wang8Chunyu Wang9Chunyu Wang10Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United StatesCenter for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United StatesDepartment of Chemistry, New York University, New York, NY, United StatesInstituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, Leioa, SpainIkerbasque, Basque Foundation for Science, Bilbao, SpainCenter for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United StatesDepartment of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United StatesSchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, United StatesCenter for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United StatesDepartment of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United StatesDepartment of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, United StatesIntramembrane-cleaving proteases (I-CLiPs) catalyze the hydrolysis of peptide bonds within the transmembrane regions of membrane protein substrates, releasing bioactive fragments that play roles in many physiological and pathological processes. Based on their catalytic mechanism and nucleophile, I-CLiPs are classified into metallo, serine, aspartyl, and glutamyl proteases. Presenilin is the most prominent among I-CLiPs, as the catalytic subunit of γ-secretase (GS) complex responsible for cleaving the amyloid precursor protein (APP) and Notch, as well as many other membrane substrates. Recent cryo-electron microscopy (cryo-EM) structures of GS provide new details on how presenilin recognizes and cleaves APP and Notch. First, presenilin transmembrane helix (TM) 2 and 6 are dynamic. Second, upon binding to GS, the substrate TM helix is unwound from the C-terminus, resulting in an intermolecular β-sheet between the substrate and presenilin. The transition of the substrate C-terminus from α-helix to β-sheet is proposed to expose the scissile peptide bond in an extended conformation, leaving it susceptible to protease cleavage. Despite the astounding new insights in recent years, many crucial questions remain unanswered regarding the inner workings of γ-secretase, however. Key unanswered questions include how the enzyme recognizes and recruits substrates, how substrates are translocated from an initial docking site to the active site, how active site aspartates recruit and coordinate catalytic water, and the nature of the mechanisms of processive trimming of the substrate and product release. Answering these questions will have important implications for drug discovery aimed at selectively reducing the amyloid load in Alzheimer’s disease (AD) with minimal side effects.https://www.frontiersin.org/article/10.3389/fnmol.2020.00065/fullI-CLiPsγ-secretasesubstrateinteractionAlzheimer’s disease |
| spellingShingle | Xinyue Liu Jing Zhao Yingkai Zhang Iban Ubarretxena-Belandia Iban Ubarretxena-Belandia Scott Forth Scott Forth Raquel L. Lieberman Chunyu Wang Chunyu Wang Chunyu Wang Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype Frontiers in Molecular Neuroscience I-CLiPs γ-secretase substrate interaction Alzheimer’s disease |
| title | Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype |
| title_full | Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype |
| title_fullStr | Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype |
| title_full_unstemmed | Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype |
| title_short | Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype |
| title_sort | substrate enzyme interactions in intramembrane proteolysis γ secretase as the prototype |
| topic | I-CLiPs γ-secretase substrate interaction Alzheimer’s disease |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2020.00065/full |
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