Misfolding-Associated Exposure of Buried Residues in Mutant Sod1 Facilitates Binding to TRAF6

Garg, Pranav; Semmler, Sabrina; Baudouin, Christophe; Velde, Christine Vande; Plotkin, Steven S.

doi:10.1016/j.bpj.2020.11.1897

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“…These mutants maintained a dimeric structure but lost some secondary conformations, which could form oligomers by means of intermolecular disulfide bridges. Additionally, the non-native homodimers in SOD1 have been discussed in molecular dynamic simulations 60 and also experimentally, 61 where the authors use NMR data to build two models for the non-native dimer. Figure 10b shows the superposition of 15 structures that most represent the dApo I simulation (all-atoms and ABF-free) when the dimer has CM−CM distances between 30.5 and 31.5 Å.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Exploring the Folding Mechanism of Dimeric Superoxide Dismutase

et al. 2023

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The Cu/Zn Human Superoxide Dismutase (SOD1) is a dimeric metalloenzyme whose genetic mutations are directly related to amyotrophic lateral sclerosis (ALS), so understanding its folding mechanism is of fundamental importance. Currently, the SOD1 dimer formation is studied via molecular dynamics simulations using a simplified structure-based model and an all-atom model. Results from the simplified model reveal a mechanism dependent on distances between monomers, which are limited by constraints to mimic concentration dependence. The stability of intermediates (during the int state) is significantly affected by this distance, as well as by the presence of two folded monomers prior to dimer formation. The kinetics of interface formation are also highly dependent on the separation distance. The folding temperature of the dimer is about 4.2% higher than that of the monomer, a value not too different from experimental data. All-atom simulations on the apo dimer give binding free energy between monomers similar to experimental values. An intermediate state is evident for the apo form at a separation distance between monomers slightly larger than the native distance which has little formed interface between monomers. We have shown that this intermediate is stabilized by non-native intra- and intercontacts.

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Section: ■ Results and Discussionmentioning

confidence: 99%