The Crystal Structure of Peroxiredoxin Asp f3 Provides Mechanistic Insight into Oxidative Stress Resistance and Virulence of Aspergillus fumigatus.
Invasive aspergillosis and other fungal infections occur in immunocompromised individuals, including patients who received blood-building stem cell transplants, patients with chronic granulomatous disease (CGD), and others. Production of reactive oxygen species (ROS) by immune cells, which incidentally is defective in CGD patients, is considered to be a fundamental process in inflammation and antifungal immune response. Here we show that the peroxiredoxin Asp f3 of Aspergillus fumigatus inactivates ROS. We report the crystal structure and the catalytic mechanism of Asp f3, a two-cysteine type peroxiredoxin. The latter exhibits a thioredoxin fold and a homodimeric structure with two intermolecular disulfide bonds in its oxidized state. Replacement of the Asp f3 cysteines with serine residues retained its dimeric structure, but diminished Asp f3's peroxidase activity, and extended the alpha-helix with the former peroxidatic cysteine residue C61 by six residues. The asp f3 deletion mutant was sensitive to ROS, and this phenotype was rescued by ectopic expression of Asp f3. Furthermore, we showed that deletion of asp f3 rendered A. fumigatus avirulent in a mouse model of pulmonary aspergillosis. The conserved expression of Asp f3 homologs in medically relevant molds and yeasts prompts future evaluation of Asp f3 as a potential therapeutic target.
Junior Research Group Evolution of Microbial Interactions, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institut, Beutenbergstrasse 11a, D-07745 Jena, Germany.
Falk
F
Hillmann
Department of Molecular Immunology, The Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Karine
K
Bagramyan
Transfer Group Anti-infectives, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institut, Beutenbergstrasse 11a, D-07745 Jena, Germany.
Maria
M
Straßburger
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institut, Beutenbergstrasse 11a, D-07745 Jena, Germany.
Thorsten
T
Heinekamp
Department of Molecular Immunology, The Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Teresa B
TB
Hong
Department of Molecular Medicine, The Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Krzysztof P
KP
Bzymek
Department of Molecular Medicine, The Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
John C
JC
Williams
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institut, Beutenbergstrasse 11a, D-07745 Jena, Germany.|Institute of Microbiology, Friedrich Schiller University Jena, D-07743 Jena, Germany.
Axel A
AA
Brakhage
Department of Molecular Immunology, The Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Markus
M
Kalkum
D000818:Animals; D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000378:metabolism* / Q000472:pathogenicity*; D018360:Crystallography, X-Ray; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry*; D017353:Gene Deletion; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D054464:Peroxiredoxins / Q000737:chemistry*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013481:Superoxides / Q000633:toxicity; D014774:Virulence
D005656:Fungal Proteins; D050505:Mutant Proteins; D013481:Superoxides; D054464:Peroxiredoxins; D009195:Peroxidase