Redox-dependent conformational transition of catalytic domain of protein disulfide isomerase indicated by crystal structure-based molecular dynamics simulation

Inagaki, K.; Satoh, Tadashi; Itoh, Satoru; Okumura, Hisashi; Kato, Koichi

doi:10.1016/j.cplett.2014.11.017

Cited by 11 publications

(19 citation statements)

References 31 publications

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“…However, the amino acid residues in β 1 form intermolecular hydrogen bonds with higher probability than those in β 2. In general, a secondary structure with more hydrogen bonds fluctuates less than that with less hydrogen bonds3132. In other words, the secondary structure with more hydrogen bonds is firmer than that with less hydrogen bonds.…”

Section: Resultsmentioning

confidence: 98%

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Okumura

Itoh

2016

Sci Rep

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Aβ amyloid fibrils, which are related to Alzheimer’s disease, have a cross-β structure consisting of two β-sheets: β1 and β2. The Aβ peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Aβ42 and Aβ40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Aβ peptide always took a closed form wherein β1 and β2 were closely spaced. The Aβ peptide fluctuated more at the odd end and took an open form wherein the two β-sheets were well separated. The differences are attributed to the stronger β-sheet formation by the β1 exposed at the even end than the β2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy.

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Section: Resultsmentioning

confidence: 98%

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Okumura

Itoh

2016

Sci Rep

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“…3a ). Due to the crystal packing, the spatial domain arrangement of the αSN-bound oxidized PDI b ′– a ′ domains was remarkably different from that of the unliganded form (PDB code: 3WT2) 25 , suggesting the dynamic nature of the interdomain substrate-binding region ( Fig. 3b ).…”

Section: Resultsmentioning

confidence: 99%

“…Expression and purification of the PDI b ′– a ′ domains (residues 208–449), b ′ domain (residues 208–335), and a ′ domain (residues 334–449) from Humicola insolens were performed as previously described 12 13 25 . To prepare the oxidized form, the purified protein (1 mg/ml) was dialyzed against 50 mM Tris-HCl (pH 8.0) containing 0.1 mM oxidized glutathione for a week.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of redox-dependent substrate binding of protein disulfide isomerase

Yagi-Utsumi

Satoh

Kato

2015

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Protein disulfide isomerase (PDI) is a multidomain enzyme, operating as an essential folding catalyst, in which the b′ and a′ domains provide substrate binding sites and undergo an open–closed domain rearrangement depending on the redox states of the a′ domain. Despite the long research history of this enzyme, three-dimensional structural data remain unavailable for its ligand-binding mode. Here we characterize PDI substrate recognition using α-synuclein (αSN) as the model ligand. Our nuclear magnetic resonance (NMR) data revealed that the substrate-binding domains of PDI captured the αSN segment Val37–Val40 only in the oxidized form. Furthermore, we determined the crystal structure of an oxidized form of the b′–a′ domains in complex with an undecapeptide corresponding to this segment. The peptide-binding mode observed in the crystal structure with NMR validation, was characterized by hydrophobic interactions on the b′ domain in an open conformation. Comparison with the previously reported crystal structure indicates that the a′ domain partially masks the binding surface of the b′ domain, causing steric hindrance against the peptide in the reduced form of the b′–a′ domains that exhibits a closed conformation. These findings provide a structural basis for the mechanism underlying the redox-dependent substrate binding of PDI.

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“…45 Recent MD studies conrmed such redox-regulation of PDI conformations, but revealed a much larger degree of exibility. 46,47 Smallangle X-ray scattering (SAXS) experiments, 48,49 including ours, 21 were also carried out to study the solution conformation of PDI. All these results suggest a hypothesis of redox-regulated substrate binding of PDI where PDI is in an open conformation in the oxidized state (in the presence of GSSG) to expose its hydrophobic substrate binding pocket, and becomes compact in the reduced form to expel the substrate away from the substrate binding site.…”

Section: Protein Exibility Of Pdimentioning

confidence: 99%

Molecular basis of rutin inhibition of protein disulfide isomerase (PDI) by combinedin silicoand experimental methods

et al. 2018

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Redox-dependent conformational transition of catalytic domain of protein disulfide isomerase indicated by crystal structure-based molecular dynamics simulation

Cited by 11 publications

References 31 publications

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations

Structural basis of redox-dependent substrate binding of protein disulfide isomerase

Molecular basis of rutin inhibition of protein disulfide isomerase (PDI) by combinedin silicoand experimental methods

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