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Article Abstract
Three of the four independently induced Ketel(D) dominantnegative female sterile mutations that identify the Drosophila importin-beta gene, originated from a C4114--> T transition and the concurrent replacement of Pro446 by Leu (P446L). CD spectroscopy of representative peptides with Pro or Leu in the crucial position revealed that upon the Pro-->Leu exchange the P446L mutant protein loses flexibility and attains most likely an open conformation. The P446L mutation abolishes RanGTP binding of the P446L mutant form of importin-beta protein and results in increased RanGDP binding ability. Notably, the P446L mutant importin-beta does not exert its dominant-negative effect on nuclear protein import and has no effect on mitotic spindle-related functions and chromosome segregation. However, it interferes with nuclear envelope formation during mitosis-to-interphase transition, revealing a novel function of importin-beta.
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Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence.
Biochem J
May 2014
*Department of Biochemistry and Biophysics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A.
Hepatic glucose phosphorylation by GK (glucokinase) is regulated by GKRP (GK regulatory protein). GKRP forms a cytosolic complex with GK followed by nuclear import and storage, leading to inhibition of GK activity. This process is initiated by low glucose, but reversed nutritionally by high glucose and fructose or pharmacologically by GKAs (GK activators) and GKRPIs (GKRP inhibitors).
View Article and Find Full Text PDFCellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk.
Diabetologia
January 2012
Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK.
Aims/hypothesis: Translation of genetic association signals into molecular mechanisms for diabetes has been slow. The glucokinase regulatory protein (GKRP; gene symbol GCKR) P446L variant, associated with inverse modulation of glucose- and lipid-related traits, has been shown to alter the kinetics of glucokinase (GCK) inhibition. As GCK inhibition is associated with nuclear sequestration, we aimed to determine whether this variant also alters the direct interaction between GKRP and GCK and their intracellular localisation.
View Article and Find Full Text PDFP446L-importin-beta inhibits nuclear envelope assembly by sequestering nuclear envelope assembly factors to the microtubules.
Eur J Cell Biol
July 2003
The University of Szeged, Faculty of Medicine, Department of Biology, Szeged, Hungary.
The P446L mutant Drosophila importin-beta (P446L-imp-beta) has been reported to prohibit--in dominant negative fashion--nuclear envelope (NE) assembly. Along elucidating the mode of action of P446L-imp-beta we studied in vitro NE assembly on Sepharose beads. While Drosophila embryo extracts support NE assembly over Sepharose beads coated with Ran, NE assembly does not take place in extracts supplied with exogenous P446L-imp-beta.
View Article and Find Full Text PDFThe importin-beta P446L dominant-negative mutant protein loses RanGTP binding ability and blocks the formation of intact nuclear envelope.
J Cell Sci
April 2002
The University of Szeged, Faculty of Medicine, Department of Biology, Somogyi B. u. 4, H-6720 Szeged, Hungary.
Three of the four independently induced Ketel(D) dominantnegative female sterile mutations that identify the Drosophila importin-beta gene, originated from a C4114--> T transition and the concurrent replacement of Pro446 by Leu (P446L). CD spectroscopy of representative peptides with Pro or Leu in the crucial position revealed that upon the Pro-->Leu exchange the P446L mutant protein loses flexibility and attains most likely an open conformation. The P446L mutation abolishes RanGTP binding of the P446L mutant form of importin-beta protein and results in increased RanGDP binding ability.
View Article and Find Full Text PDF