Abstract
Myoglobin is an α-helical globular protein containing two highly conserved tryptophanyl residues at positions 7 and 14 in the N-terminal region. The simultaneous substitution of the two residues impairs the productive folding of the protein making the polypeptide chain highly prone to aggregate forming amyloid fibrils at physiological pH and room temperature. The role played by tryptophanyl residues in driving the productive folding process was investigated by providing structural details at low resolution of compact intermediate of three mutated apomyoglobins, i.e., W7F, W14F and the amyloid forming mutant W7FW14F.
In particular, we followed the hydrogen/deuterium exchange rate of protein segments using proteolysis with pepsin followed by mass spectrometry analysis. The results revealed significant differences in the N-terminal region, consisting in an alteration of the physico-chemical properties of the 7-11 segment for W7F and in an increase of local flexibility of the12-29 segment for W14F. In the double trypthophanyl substituted mutant, these effects are additive and impair the formation of native-like contacts and favour inter-chain interactions leading to protein aggregation and amyloid formation at physiological pH.
Keywords: Amyloid aggregation, apomyoglobin, H/D exchanges, protein folding, protein misfolding, W-F substitution.
Protein & Peptide Letters
Title:W-F Substitutions in Apomyoglobin Increase the Local Flexibility of the N-terminal Region Causing Amyloid Aggregation: A H/D Exchange Study
Volume: 20 Issue: 8
Author(s): Giuseppe Infusini, Clara Iannuzzi, Silvia Vilasi, Rosa Maritato, Leila Birolo, Daniela Pagnozzi, Piero Pucci, Gaetano Irace and Ivana Sirangelo
Affiliation:
Keywords: Amyloid aggregation, apomyoglobin, H/D exchanges, protein folding, protein misfolding, W-F substitution.
Abstract: Myoglobin is an α-helical globular protein containing two highly conserved tryptophanyl residues at positions 7 and 14 in the N-terminal region. The simultaneous substitution of the two residues impairs the productive folding of the protein making the polypeptide chain highly prone to aggregate forming amyloid fibrils at physiological pH and room temperature. The role played by tryptophanyl residues in driving the productive folding process was investigated by providing structural details at low resolution of compact intermediate of three mutated apomyoglobins, i.e., W7F, W14F and the amyloid forming mutant W7FW14F.
In particular, we followed the hydrogen/deuterium exchange rate of protein segments using proteolysis with pepsin followed by mass spectrometry analysis. The results revealed significant differences in the N-terminal region, consisting in an alteration of the physico-chemical properties of the 7-11 segment for W7F and in an increase of local flexibility of the12-29 segment for W14F. In the double trypthophanyl substituted mutant, these effects are additive and impair the formation of native-like contacts and favour inter-chain interactions leading to protein aggregation and amyloid formation at physiological pH.
Export Options
About this article
Cite this article as:
Infusini Giuseppe, Iannuzzi Clara, Vilasi Silvia, Maritato Rosa, Birolo Leila, Pagnozzi Daniela, Pucci Piero, Irace Gaetano and Sirangelo Ivana, W-F Substitutions in Apomyoglobin Increase the Local Flexibility of the N-terminal Region Causing Amyloid Aggregation: A H/D Exchange Study, Protein & Peptide Letters 2013; 20 (8) . https://dx.doi.org/10.2174/0929866511320080006
DOI https://dx.doi.org/10.2174/0929866511320080006 |
Print ISSN 0929-8665 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5305 |
- 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
Related Articles
-
Protein Aggregation: Elucidation of the Mechanism and Determination of Associated Thermodynamic and Kinetic Parameters
Current Physical Chemistry Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors
Current Topics in Medicinal Chemistry Lithium and its Neuroprotective and Neurotrophic Effects: Potential Treatment for Post-Ischemic Stroke Sequelae
Current Drug Targets Meet Our Editorial Board Member
Current Alzheimer Research Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress
Current Drug Metabolism Editorial (Thematic Issue: GABAergic Modulation as Treatment Strategy: Consideration of Several Diseases)
Current Pharmaceutical Design Effects of Erythropoietin on Brain Function
Current Pharmaceutical Biotechnology Anti-Oxidants in Parkinson’s Disease Therapy: A Critical Point of View
Current Neuropharmacology Amyloid β Accumulation Assessed with <sup>11</sup>C-Pittsburgh Compound B PET and Postmortem Neuropathology
Current Alzheimer Research The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View
Current Alzheimer Research Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders
Mini-Reviews in Medicinal Chemistry Vascular Endothelial Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress
Current Drug Targets Amyloid-Related Biomarkers for Alzheimers Disease
Current Medicinal Chemistry Resveratrol and Lifespan in Model Organisms
Current Medicinal Chemistry Prevention and Treatment for Chemotherapy-Induced Peripheral Neuropathy: Therapies Based on CIPN Mechanisms
Current Neuropharmacology Targeting Angiogenic Pathways in Colorectal Cancer: Complexities, Challenges and Future Directions
Current Drug Targets Metabotropic Glutamate Receptors in the Control of Neuronal Activity and as Targets for Development of Anti-Epileptogenic Drugs
Current Medicinal Chemistry Experimental Research on Nitric Oxide and the Therapy of Alzheimer Disease: A Challenging Bridge
CNS & Neurological Disorders - Drug Targets Pharmacological Applications of Antioxidants: Lights and Shadows
Current Drug Targets PPARs in Neurodegenerative and Neuroinflammatory Pathways
Current Alzheimer Research