The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein (Articolo in rivista)

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  • The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein (Articolo in rivista) (literal)
Anno
  • 2002-01-01T00:00:00+01:00 (literal)
Alternative label
  • Ilari A (1), Johnson KA (2), Nastopoulos V (3), Verzili D (1), Zamparelli C (2), Colotti G (1), Tsernoglou D (2), Chiancone E. (1,2) (2002)
    The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein
    in Journal of Molecular Biology
    (literal)
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  • Ilari A (1), Johnson KA (2), Nastopoulos V (3), Verzili D (1), Zamparelli C (2), Colotti G (1), Tsernoglou D (2), Chiancone E. (1,2) (literal)
Pagina inizio
  • 447 (literal)
Pagina fine
  • 458 (literal)
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  • The interdisciplinary level of the paper is noteworthy: although the techniques used are only of physico-chemical character, the topic has important pathological implications. It is published in an authoritative peer-reviewed journal, Journal of Molecular Biology (impact factor year 2002: 5.826), and has been cited 6 times since its publication. (literal)
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  • 29 (literal)
Rivista
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  • E. Chiancone, Direttore IBPM (literal)
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  • The paper presents crystal structure of the calcium-binding domain of sorcin, a penta-EF hand (PEF) two-domain protein that upon Ca2+ binding translocates reversibly from cytosol to membranes, where it interacts with different target proteins. In muscle cells, the sorcin participates in excitation-contraction coupling through the interaction with the ryanodine receptor (RyR), the Na+-Ca2+ exchanger (NCX) and the a1-subunit of L-type Ca2+ channels. The structure of the calcium-binding domain provides insight into the Ca2+- induced conformational changes that lead to target protein recognition. In the model, the N- and C-terminal domains interact with each other in the Ca2+-free form and these interactions are weakened upon Ca2+ binding. Further, in the calcium-free form the N-terminal domain covers a large hydrophobic surface which includes the two tryptophan residues on the D helix. Upon Ca2+ binding, this hydrophobic surface becomes accessible for target protein recognition, since loosening of the interactions between the two domains permits their reorientation. This mechanism may be applicable to all PEF proteins. The outcome of the paper provides an explanation in molecular terms for a recently described form of familial hypertrophic cardiomyopathy that is associated with a missense mutation at the end of the D-helix (F112L) of the sorcin molecule. (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • 1. CNR (Istituto di Biologia e Patologia Molecolari) 2. Uni Sapienza (Dipartimento di Scienze Biochimiche “A. Rossi Fanelli”) 3. Uni Patrasso (Grecia, Dipartimento di Chimica) (literal)
Titolo
  • The crystal structure of the sorcin calcium binding domain provides a model of Ca2+-dependent processes in the full-length protein (literal)
Abstract
  • Sorcin is a 21.6 kDa calcium binding protein, expressed in a number of mammalian tissues that belongs to the small, recently identified penta-EF-hand (PEF) family. Like all members of this family, sorcin undergoes a Ca2+-dependent translocation from cytosol to membranes where it binds to target proteins. For sorcin, the targets differ in different tissues, indicating that it takes part in a number of Ca2+-regulated processes. The sorcin monomer is organized in two domains like in all PEF proteins: a flexible, hydrophobic, glycine-rich N-terminal region and a calcium binding C-terminal domain. In vitro, the PEF proteins are dimeric in their Ca2+-free form, but have a marked tendency to precipitate when bound to calcium. Stabilization of the dimeric structure is achieved by pairing of the uneven EF-hand, EF5. Sorcin can also form tetramers at acid pH. The sorcin calcium binding domain (SCBD, residues 33-198) expressed in Escherichia coli was crystallized in the Ca2+-free form. The structure was solved by molecular replacement and was refined to 2.2 A with a crystallographic R-factor of 22.4 %. Interestingly, the asymmetric unit contains two dimers. The structure of the SCBD leads to a model that explains the solution properties and describes the Ca2+-induced conformational changes. Phosphorylation studies show that the N-terminal domain hinders phosphorylation of SCBD, i.e. the rate of phosphorylation increased twofold in the absence of the N-terminal region. In addition, previous fluorescence studies indicated that hydrophobic residues are exposed to solvent upon Ca2+ binding to full-length sorcin. The model accounts for these data by proposing that Ca2+ binding weakens the interactions between the two domains and leads to their reorientation, which exposes hydrophobic regions facilitating the Ca2+-dependent binding to target proteins at or near membranes. (literal)
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