Effect on intrinsic peroxidase activity of substituting coevolved residues from Ω-loop C of human cytochrome c into yeast iso-1-cytochrome c

Frederick, Ariel; Thompson, Sidney L; Vakharia, Zahra M; Cherney, Melisa M.; Lei, Haotian; Evenson, Garrett; Bowler, Bruce E.

doi:10.1016/j.jinorgbio.2022.111819

Cited by 5 publications

(5 citation statements)

References 89 publications

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“…These results mirror the pattern we observed during simulations of the Lys73-ligated alkaline conformer. The dynamics of Ω-loop C appear to play a role in the rearrangement of Ω-loop D, readily apparent for the Lys73-ligated conformer with simulations in this work and prior mutational studies. ,,− The extent of the dynamic nature of Ω-loop C may depend on the coordinating residue (Lys73 or Lys79) and associated structural rearrangements, as well as additional structural elements, such as formation of a dimer.…”

Section: Discussionmentioning

confidence: 54%

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Applications of the Newly Developed Force-Field Parameters Uncover a Dynamic Nature of Ω-Loop C in the Lys-Ligated Alkaline Form of Cytochrome c

Deng,

Carnevale,

Ditchfield

et al. 2024

J. Phys. Chem. B

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Section: Discussionmentioning

confidence: 54%

“…The rearrangement of both Ω-loops C and D observed in our simulations, however, could explain such an exposure. Because the unfolding of these low-stability loops can facilitate the solvent access to the heme crevice, , groups in the interior of the protein could get more readily deprotonated, triggering the transition. , …”

Section: Discussionmentioning

confidence: 99%

Applications of the Newly Developed Force-Field Parameters Uncover a Dynamic Nature of Ω-Loop C in the Lys-Ligated Alkaline Form of Cytochrome c

Deng,

Carnevale,

Ditchfield

et al. 2024

J. Phys. Chem. B

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“…For more than 80 years, monomeric Cyt c has been known to undergo a conformational transition in the alkaline pH regime . The alkaline conformer of monomeric Cyt c has gained particular interest because the stability of Ω-loop D generally correlates well with the thermodynamics of the alkaline transition. , Furthermore, there is often, ,− , but not always, a correlation between the stability of Cyt c with respect to the alkaline conformational transition and the accessibility of states which promote peroxidase activity. However, it is important to note that lysine is a much stronger ligand than methionine for Fe(III) in an aqueous environment, , so ultimately the alkaline conformer shuts off peroxidase activity. ,,, …”

Section: Resultsmentioning

confidence: 99%

“…To allow Cyt c to perform peroxidase activity, Met80 must dissociate from the heme to create an open heme coordination site . Much research has focused on the role played by the two least stable substructures of Cyt c (Ω-loop C, residues 40–57 and Ω-loop D, residues 70–85) in regulating access to the heme. − However, while the dynamics of these loops are undoubtedly important, recent work indicates that activation of the peroxidase activity of Cyt c is linked to oxidative damage to one or more amino acid residues of Cyt c . − …”

Section: Introductionmentioning

confidence: 99%

Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity

2022

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A 2.08 Å structure of an alkaline conformer of the domain-swapped dimer of K72A human cytochrome c (Cytc) crystallized at pH 9.9 is presented. In the structure, Lys79 is ligated to the heme. All other domain-swapped dimer structures of Cytc have water bound to this coordination site. Part of Ω-loop D (residues 70–85) forms a flexible linker between the subunits in other Cytc domain-swapped dimer structures but instead converts to a helix in the alkaline conformer of the dimer combining with the C-terminal helix to form two 26-residue helices that bracket both sides of the dimer. The alkaline transition of the K72A human dimer monitored at both 625 nm (high spin heme) and 695 nm (Met80 ligation) yields midpoint pH values of 6.6 and 7.6, respectively, showing that the Met80 → Lys79 and high spin to low spin transitions are distinct. The dimer peroxidase activity increases rapidly below pH 7, suggesting that population of the high spin form of the heme is what promotes peroxidase activity. Comparison of the structures of the alkaline dimer and the neutral pH dimer shows that the neutral pH conformer has a better electrostatic surface for binding to a cardiolipin-containing membrane and provides better access for small molecules to the heme iron. Given that the pH of mitochondrial cristae ranges from 6.9 to 7.2, the alkaline transition of the Cytc dimer could provide a conformational switch to tune the peroxidase activity of Cytc that oxygenates cardiolipin in the early stages of apoptosis.

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“…This work makes knowledge of cognate ligands and their binding sites in UniProtKB easier to find and access. It provides improved support for the design of biochemical experiments ( Fleischhacker et al , 2015 ; Frederick et al , 2022 ) and computational approaches ( Das et al , 2021 ; Littmann et al , 2021 ; Wehrspan et al , 2022 ; Wu et al , 2018 ) to elucidate protein functions and interactions, and enhances interoperability with other resources providing knowledge of cognate ligands such as PDBe ( Mukhopadhyay et al , 2019 ), BioLiP ( Yang et al , 2013 ), FireDB ( Maietta et al , 2014 ), MetalPDB ( Putignano et al , 2018 ) and PDBBind ( Liu et al , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Annotation of biologically relevant ligands in UniProtKB using ChEBI

et al. 2022

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Motivation To provide high quality, computationally tractable annotation of binding sites for biologically relevant (cognate) ligands in UniProtKB using the chemical ontology ChEBI (Chemical Entities of Biological Interest), to better support efforts to study and predict functionally relevant interactions between protein sequences and structures and small molecule ligands. Results We structured the data model for cognate ligand binding site annotations in UniProtKB and performed a complete reannotation of all cognate ligand binding sites using stable unique identifiers from ChEBI, which we now use as the reference vocabulary for all such annotations. We developed improved search and query facilities for cognate ligands in the UniProt website, REST API and SPARQL endpoint that leverage the chemical structure data, nomenclature, and classification that ChEBI provides. Availability Binding site annotations for cognate ligands described using ChEBI are available for UniProtKB protein sequence records in several formats (text, XML, and RDF), and are freely available to query and download through the UniProt website (www.uniprot.org), REST API (www.uniprot.org/help/api), SPARQL endpoint (sparql.uniprot.org/), and FTP site (https://ftp.uniprot.org/pub/databases/uniprot/). Supplementary information Supplementary data are available at Bioinformatics online.

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Effect on intrinsic peroxidase activity of substituting coevolved residues from Ω-loop C of human cytochrome c into yeast iso-1-cytochrome c

Cited by 5 publications

References 89 publications

Applications of the Newly Developed Force-Field Parameters Uncover a Dynamic Nature of Ω-Loop C in the Lys-Ligated Alkaline Form of Cytochrome c

Applications of the Newly Developed Force-Field Parameters Uncover a Dynamic Nature of Ω-Loop C in the Lys-Ligated Alkaline Form of Cytochrome c

Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity

Annotation of biologically relevant ligands in UniProtKB using ChEBI

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