Abstract
γ-Secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid β-protein precursor, involved in Alzheimers disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteolysis into two subunits, each of which contributes one aspartate to the active site of an aspartyl protease. The protease contains an initial docking site for substrate, where it binds prior to passing between the two presenilin subunits to the internal water-containing active site. The extracellular region of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Modulation of APP processing without interfering with Notch signaling is an important therapeutic goal, and allosteric sites on the protease allow such selective modulation. A better structural and mechanistic understanding of γ-secretase should ultimately allow structure-based design of more potent and selective modulators.
Current Topics in Medicinal Chemistry
Title: γ-Secretase: Structure, Function, and Modulation for Alzheimers Disease
Volume: 8 Issue: 1
Author(s): Michael S. Wolfe
Affiliation:
Abstract: γ-Secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid β-protein precursor, involved in Alzheimers disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteolysis into two subunits, each of which contributes one aspartate to the active site of an aspartyl protease. The protease contains an initial docking site for substrate, where it binds prior to passing between the two presenilin subunits to the internal water-containing active site. The extracellular region of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Modulation of APP processing without interfering with Notch signaling is an important therapeutic goal, and allosteric sites on the protease allow such selective modulation. A better structural and mechanistic understanding of γ-secretase should ultimately allow structure-based design of more potent and selective modulators.
Export Options
About this article
Cite this article as:
Wolfe S. Michael, γ-Secretase: Structure, Function, and Modulation for Alzheimers Disease, Current Topics in Medicinal Chemistry 2008; 8 (1) . https://dx.doi.org/10.2174/156802608783334024
DOI https://dx.doi.org/10.2174/156802608783334024 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nutrition, Brain Aging, and Alzheimers Disease
Current Nutrition & Food Science Commentary: Death Associated Protein Kinase 1: A Perp in Cerebral Ischemia
CNS & Neurological Disorders - Drug Targets Recent Advances in the Rational Drug Design Based on Multi-target Ligands
Current Medicinal Chemistry Ectodomain Structures of the CGRP and AM Receptors
Current Protein & Peptide Science L-Carnitine - Metabolic Functions and Meaning in Humans Life
Current Drug Metabolism Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications
Current Molecular Medicine The Assessment of Some Metabolic Markers by Combination of Ursolic Acid Supplementation and Resistance Training in Young Older Obese Women
Endocrine, Metabolic & Immune Disorders - Drug Targets The Effect of Acute Hypoxia on Excitability in the Heart and the L-Type Calcium Channel as a Therapeutic Target
Current Drug Discovery Technologies Mechanism of Organophosphates (Nerve Gases and Pesticides) and Antidotes: Electron Transfer and Oxidative Stress
Current Medicinal Chemistry Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review
Current Topics in Medicinal Chemistry Epidural Analgesia in the Post-Anaesthesia Care Unit
Current Drug Targets Functional Genomics of Brain Aging and Alzheimers Disease: Focus on Selective Neuronal Vulnerability
Current Genomics Innate Immune System Modulation During Aging: Contributions of Macrophages and Dendritic Cells
Current Immunology Reviews (Discontinued) Current Understanding of Dyslexia and Pilot Data on Efficacy of a Mindfulness Based Psychotherapy (MBR-RAM) Model
Adolescent Psychiatry Cervical Cancer Diagnosis: Insights into Biochemical Biomarkers and Imaging Techniques
Combinatorial Chemistry & High Throughput Screening Impaired Spatial Memory after Ketamine Administration in Chronic Low Doses
Current Neuropharmacology FMRI and Multiple Sclerosis
Current Medical Imaging Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease
Current Alzheimer Research A Computational View of COX-2 Inhibition
Anti-Cancer Agents in Medicinal Chemistry Methods for Hydroxamic Acid Synthesis
Current Organic Chemistry