Interaction of bestrophin-1 and Ca2+ channel β-subunits: identification of new binding domains on the bestrophin-1 C-terminus.

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urn:nbn:de:bvb:355-epub-237514 Copy

Milenkovic, Vladimir M. ; Krejcova, Sarka ; Reichhart, Nadine ; Wagner, Andrea ; Strauss, Olaf

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Date of publication of this fulltext: 11 Apr 2012 09:07

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Item type:	Article
Journal or Publication Title:	PloS one
Volume:	6
Number of Issue or Book Chapter:	4
Page Range:	e19364
Date:	29 April 2011
Institutions:	Medicine > Lehrstuhl für Augenheilkunde
Identification Number:	Value Type 15530640 PubMed ID 10.1371/journal.pone.0019364 DOI
Classification:	Notation Type Amino Acid Motifs MESH Animals MESH CHO Cells MESH Calcium Channels/chemistry MESH Chloride Channels/chemistry MESH Cricetinae MESH Cricetulus MESH Eye Proteins/chemistry MESH HEK293 Cells MESH Humans MESH Microscopy, Confocal/methods MESH Patch-Clamp Techniques MESH Protein Binding MESH Protein Conformation MESH Protein Structure, Secondary MESH Protein Structure, Tertiary MESH
Dewey Decimal Classification:	600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	23751

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Abstract

Bestrophin-1 modulates currents through voltage-dependent L-type Ca(2+) channels by physically interacting with the β-subunits of Ca(2+) channels. The main function of β-subunits is to regulate the number of pore-forming Ca(V)-subunits in the cell membrane and modulate Ca(2+) channel currents. To understand the influence of full-length bestrophin-1 on β-subunit function, we studied binding and ...

Abstract

Bestrophin-1 modulates currents through voltage-dependent L-type Ca(2+) channels by physically interacting with the β-subunits of Ca(2+) channels. The main function of β-subunits is to regulate the number of pore-forming Ca(V)-subunits in the cell membrane and modulate Ca(2+) channel currents. To understand the influence of full-length bestrophin-1 on β-subunit function, we studied binding and localization of bestrophin-1 and Ca(2+) channel subunits, together with modulation of Ca(V)1.3 Ca(2+) channels currents. In heterologeous expression, bestrophin-1 showed co-immunoprecipitation with either, β3-, or β4-subunits. We identified a new highly conserved cluster of proline-rich motifs on the bestrophin-1 C-terminus between amino acid position 468 and 486, which enables possible binding to SH3-domains of β-subunits. A bestrophin-1 that lacks these proline-rich motifs (ΔCT-PxxP bestrophin-1) showed reduced efficiency to co-immunoprecipitate with β3 and β4-subunits. In the presence of ΔCT-PxxP bestrophin-1, β4-subunits and Ca(V)1.3 subunits partly lost membrane localization. Currents from Ca(V)1.3 subunits were modified in the presence of β4-subunit and wild-type bestrophin-1: accelerated time-dependent activation and reduced current density. With ΔCTPxxP bestrophin-1, currents showed the same time-dependent activation as with wild-type bestrophin-1, but the current density was further reduced due to decreased number of Ca(2+) channels proteins in the cell membrane. In summary, we described new proline-rich motifs on bestrophin-1 C-terminus, which help to maintain the ability of β-subunits to regulate surface expression of pore-forming Ca(V) Ca(2+)-channel subunits.

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