Metal-driven operation of the human large-conductance voltage- and Ca2+-dependent potassium channel (BK) gating ring apparatus

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Javaherian, Anoosh D.Division of Molecular Medicine, Department of Anesthesiolog, David Geffen School of Medicine, UCLA, Los Angeles, USA (författare)

Metal-driven operation of the human large-conductance voltage- and Ca2+-dependent potassium channel (BK) gating ring apparatus

Artikel/kapitelEngelska2011

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American Society for Biochemistry and Molecular Biology,2011
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LIBRIS-ID:oai:DiVA.org:liu-162176
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-162176URI
https://doi.org/10.1074/jbc.M111.235234DOI

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Språk:engelska
Sammanfattning på:engelska

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Large-conductance voltage- and Ca2+-dependent K+ (BK, also known as MaxiK) channels are homo-tetrameric proteins with a broad expression pattern that potently regulate cellular excitability and Ca2+ homeostasis. Their activation results from the complex synergy between the transmembrane voltage sensors and a large (>300 kDa) C-terminal, cytoplasmic complex (the “gating ring”), which confers sensitivity to intracellular Ca2+ and other ligands. However, the molecular and biophysical operation of the gating ring remains unclear. We have used spectroscopic and particle-scale optical approaches to probe the metal-sensing properties of the human BK gating ring under physiologically relevant conditions. This functional molecular sensor undergoes Ca2+- and Mg2+-dependent conformational changes at physiologically relevant concentrations, detected by time-resolved and steady-state fluorescence spectroscopy. The lack of detectable Ba2+-evoked structural changes defined the metal selectivity of the gating ring. Neutralization of a high-affinity Ca2+-binding site (the “calcium bowl”) reduced the Ca2+ and abolished the Mg2+ dependence of structural rearrangements. In congruence with electrophysiological investigations, these findings provide biochemical evidence that the gating ring possesses an additional high-affinity Ca2+-binding site and that Mg2+ can bind to the calcium bowl with less affinity than Ca2+. Dynamic light scattering analysis revealed a reversible Ca2+-dependent decrease of the hydrodynamic radius of the gating ring, consistent with a more compact overall shape. These structural changes, resolved under physiologically relevant conditions, likely represent the molecular transitions that initiate the ligand-induced activation of the human BK channel.

Ämnesord och genrebeteckningar

NATURVETENSKAP Biologi Strukturbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Structural Biology hsv//eng

Biuppslag (personer, institutioner, konferenser, titlar ...)

Yusifov, TalehDivision of Molecular Medicine, Department of Anesthesiolog, David Geffen School of Medicine, UCLA, Los Angeles, USA (författare)
Pantazis, AntoniosDivision of Molecular Medicine, Department of Anesthesiolog, David Geffen School of Medicine, UCLA, Los Angeles, USA(Swepub:liu)antpa45 (författare)
Franklin, SarahDivision of Molecular Medicine, Department of Anesthesiolog, David Geffen School of Medicine, UCLA, Los Angeles, USA (författare)
Gandhi, Chris S.Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA (författare)
Olcese, Riccardoivision of Molecular Medicine, Department of Anesthesiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, USA (författare)
Division of Molecular Medicine, Department of Anesthesiolog, David Geffen School of Medicine, UCLA, Los Angeles, USADivision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA (creator_code:org_t)

Sammanhörande titlar

Ingår i:Journal of Biological Chemistry: American Society for Biochemistry and Molecular Biology286:23, s. 20701-207090021-92581083-351X

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Av författaren/redakt...: Javaherian, Anoo ...; Yusifov, Taleh; Pantazis, Antoni ...; Franklin, Sarah; Gandhi, Chris S.; Olcese, Riccardo

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Av lärosätet: Linköpings universitet

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