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  1. Article: Conformational stability, dynamics and function of human frataxin: Tryptophan side chain interplay

    Espeche, Lucía D. / Sewell, Karl Ellioth / Castro, Ignacio H. / Capece, Luciana / Pignataro, María Florencia / Dain, Liliana / Santos, Javier

    Archives of biochemistry and biophysics. 2022 Jan. 15, v. 715

    2022  

    Abstract: In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron–sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a ... ...

    Abstract In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron–sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a glycine: W155G, W168G and W173G. As expected, given its localization in the assembly site, W155G was not able to activate the desulfurase activity of the supercomplex for iron–sulfur cluster assembly. In turn, W168G, which was significantly more unstable than W155G, was fully active. W173G, which was highly unstable as W168G, showed a significantly decreased activity, only slightly higher than W155G. As W168G and W173G were highly sensitive to proteolysis, we investigated the protein motions by molecular dynamic simulations. We observed that W173G may display altered motions at the Trp155 site. Furthermore, we revealed a H-bond network in which Trp155 takes part, involving residues Gln148, Asn151, Gln153 and Arg165. We suggest that this motion modulation that specifically alters the population of different Trp155 rotamers can be directly transferred to the assembly site, altering the dynamics of the ISCU His137 key residue. This hypothesis was also contrasted by means of molecular dynamic simulations of frataxin in the context of the complete supercomplex. We propose that the supercomplex requires very definite motions of Trp155 to consolidate the assembly site.
    Keywords biophysics ; humans ; neurodegenerative diseases ; proteolysis ; tryptophan
    Language English
    Dates of publication 2022-0115
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2021.109086
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  2. Article ; Online: Conformational stability, dynamics and function of human frataxin: Tryptophan side chain interplay.

    Espeche, Lucía D / Sewell, Karl Ellioth / Castro, Ignacio H / Capece, Luciana / Pignataro, María Florencia / Dain, Liliana / Santos, Javier

    Archives of biochemistry and biophysics

    2021  Volume 715, Page(s) 109086

    Abstract: In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron-sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a ... ...

    Abstract In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron-sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a glycine: W155G, W168G and W173G. As expected, given its localization in the assembly site, W155G was not able to activate the desulfurase activity of the supercomplex for iron-sulfur cluster assembly. In turn, W168G, which was significantly more unstable than W155G, was fully active. W173G, which was highly unstable as W168G, showed a significantly decreased activity, only slightly higher than W155G. As W168G and W173G were highly sensitive to proteolysis, we investigated the protein motions by molecular dynamic simulations. We observed that W173G may display altered motions at the Trp155 site. Furthermore, we revealed a H-bond network in which Trp155 takes part, involving residues Gln148, Asn151, Gln153 and Arg165. We suggest that this motion modulation that specifically alters the population of different Trp155 rotamers can be directly transferred to the assembly site, altering the dynamics of the ISCU His137 key residue. This hypothesis was also contrasted by means of molecular dynamic simulations of frataxin in the context of the complete supercomplex. We propose that the supercomplex requires very definite motions of Trp155 to consolidate the assembly site.
    MeSH term(s) Humans ; Iron-Binding Proteins/chemistry ; Iron-Binding Proteins/genetics ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Mutation ; Protein Conformation ; Protein Stability ; Tryptophan/chemistry ; Frataxin
    Chemical Substances Iron-Binding Proteins ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 2021-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2021.109086
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  3. Article ; Online: Structure of the Human ACP-ISD11 Heterodimer.

    Herrera, María Georgina / Noguera, Martín Ezequiel / Sewell, Karl Ellioth / Agudelo Suárez, William Armando / Capece, Luciana / Klinke, Sebastián / Santos, Javier

    Biochemistry

    2019  Volume 58, Issue 46, Page(s) 4596–4609

    Abstract: In recent years, the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved ... ...

    Abstract In recent years, the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well-known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 Å resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds, and apolar interactions. The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the NFS1/ACP-ISD11 core complex was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamics simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to that found in the context of the (NFS1/ACP-ISD11)
    MeSH term(s) Crystallography, X-Ray ; Electron Transport Complex I/chemistry ; Electron Transport Complex I/metabolism ; Humans ; Hydrogen Bonding ; Iron-Regulatory Proteins/chemistry ; Iron-Regulatory Proteins/metabolism ; Models, Molecular ; Protein Conformation ; Protein Folding ; Protein Multimerization
    Chemical Substances Iron-Regulatory Proteins ; LYRM4 protein, human ; NDUFAB1 protein, human ; Electron Transport Complex I (EC 7.1.1.2)
    Language English
    Publishing date 2019-11-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.9b00539
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
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  4. Article: Structure of the Human ACP-ISD11 Heterodimer

    Herrera, María Georgina / Noguera, Martín Ezequiel / Sewell, Karl Ellioth / Agudelo Suárez, William Armando / Capece, Luciana / Klinke, Sebastián / Santos, Javier

    Biochemistry. 2019 Oct. 30, v. 58, no. 46

    2019  

    Abstract: In recent years, the mammalian mitochondrial protein complex for iron–sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved ... ...

    Abstract In recent years, the mammalian mitochondrial protein complex for iron–sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well-known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 Å resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds, and apolar interactions. The 4′-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the NFS1/ACP-ISD11 core complex was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamics simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to that found in the context of the (NFS1/ACP-ISD11)₂ supercomplex core, which contains the Escherichia coli ACP instead of the human variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11 complex may fold independently and, after that, the NFS1 dimer would be stabilized.
    Keywords Escherichia coli ; cysteine ; enzymes ; human diseases ; humans ; hydrogen bonding ; metabolism ; mitochondria ; molecular dynamics ; mutation ; proteins
    Language English
    Dates of publication 2019-1030
    Size p. 4596-4609.
    Publishing place American Chemical Society
    Document type Article
    Note NAL-light
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.9b00539
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: Frataxin Structure and Function.

    Castro, Ignacio Hugo / Pignataro, María Florencia / Sewell, Karl Ellioth / Espeche, Lucía Daniela / Herrera, María Georgina / Noguera, Martín Ezequiel / Dain, Liliana / Nadra, Alejandro Daniel / Aran, Martín / Smal, Clara / Gallo, Mariana / Santos, Javier

    Sub-cellular biochemistry

    2020  Volume 93, Page(s) 393–438

    Abstract: Mammalian frataxin is a small mitochondrial protein involved in iron sulfur cluster assembly. Frataxin deficiency causes the neurodegenerative disease Friedreich's Ataxia. Valuable knowledge has been gained on the structural dynamics of frataxin, metal- ... ...

    Abstract Mammalian frataxin is a small mitochondrial protein involved in iron sulfur cluster assembly. Frataxin deficiency causes the neurodegenerative disease Friedreich's Ataxia. Valuable knowledge has been gained on the structural dynamics of frataxin, metal-ion-protein interactions, as well as on the effect of mutations on protein conformation, stability and internal motions. Additionally, laborious studies concerning the enzymatic reactions involved have allowed for understanding the capability of frataxin to modulate Fe-S cluster assembly function. Remarkably, frataxin biological function depends on its interaction with some proteins to form a supercomplex, among them NFS1 desulfurase and ISCU, the scaffolding protein. By combining multiple experimental tools including high resolution techniques like NMR and X-ray, but also SAXS, crosslinking and mass-spectrometry, it was possible to build a reliable model of the structure of the desulfurase supercomplex NFS1/ACP-ISD11/ISCU/frataxin. In this chapter, we explore these issues showing how the scientific view concerning frataxin structure-function relationships has evolved over the last years.
    MeSH term(s) Friedreich Ataxia/genetics ; Humans ; Iron-Binding Proteins/chemistry ; Iron-Binding Proteins/genetics ; Iron-Binding Proteins/metabolism ; Scattering, Small Angle ; Structure-Activity Relationship ; X-Ray Diffraction ; Frataxin
    Chemical Substances Iron-Binding Proteins
    Language English
    Publishing date 2020-01-11
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 0306-0225 ; 0096-8757
    ISSN 0306-0225 ; 0096-8757
    DOI 10.1007/978-3-030-28151-9_13
    Database MEDical Literature Analysis and Retrieval System OnLINE

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