Abstract
Human manganese superoxide dismutase is a critical oxidoreductase found in the mitochondrial matrix. Concerted proton and electron transfers are used by the enzyme to rid the mitochondria of O2•−. The mechanisms of concerted transfer enzymes are typically unknown due to the difficulties in detecting the protonation states of specific residues and solvent molecules at particular redox states. Here, neutron diffraction of two redox-controlled manganese superoxide dismutase crystals reveal the all-atom structures of Mn3+ and Mn2+ enzyme forms. The structures deliver direct data on protonation changes between oxidation states of the metal. Observations include glutamine deprotonation, the involvement of tyrosine and histidine with altered pKas, and four unusual strong-short hydrogen bonds, including a low barrier hydrogen bond. We report a concerted proton and electron transfer mechanism for human manganese superoxide dismutase from the direct visualization of active site protons in Mn3+ and Mn2+ redox states.
| Original language | English |
|---|---|
| Article number | 2079 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2021 |
Funding
We would like to thank Dr. Tymofii Y. Nikolaienko for his support in orbital analysis and utilization of the JANPA software as well as Jeffrey L. Lovelace for his computational aid. We are thankful for the insight obtained from Dr. Andrey Kovalevsky’s expertise of inorganic and quantum chemistry as well as his time spent facilitating valuable discussions. We are grateful for the constructive feedback and advice given by Dr. Timothy C. Mueser and Dr. Joseph D. Ng. We thank Scott R. Trickel and Carol Kolar for useful discussions and technical assistance. This research was supported by NASA EPSCoR (NE-80NSSC17M0030 and NE-NNX15AM82A). The UNMC Structural Biology Core Facility was funded by the Fred and Pamela Buffett NCI Cancer Center Support Grant (P30CA036727). L.C. acknowledges support by the NIH (R01-GM071939). The research at Oak Ridge National Laboratory (ORNL) Spallation Neutron Source was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. This research used resources at the Second Target Station, which is a DOE Office of Science User Facilities Construction Project at ORNL. The Office of Biological and Environmental Research supported research at ORNL Center for Structural Molecular Biology (CSMB) using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. Quantum computations were completed utilizing the Holland Computing Center of the University of Nebraska, which receives support from the Nebraska Research Initiative.