scholarly journals Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3β) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein

2020 ◽  
Author(s):  
Stephanie Saundh ◽  
Debasis Patnaik ◽  
Steve Gagné ◽  
Josh Bishop ◽  
Sean Lipsit ◽  
...  

ABSTRACTGlycogen Synthase Kinase 3-beta (GSK3β) is a critical regulator of several cellular pathways involved in neuroplasticity and is a potential target for neurotherapeutic development in the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3β have been focused on developing small molecule inhibitors that compete with ATP through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The Disrupted in Schizophrenia (DISC1) protein, has previously been shown to bind and inhibit GSK3β activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3β in a non-competitive mode that is distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3β: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3β binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3β.

1994 ◽  
Vol 14 (12) ◽  
pp. 7909-7919 ◽  
Author(s):  
K S Bowdish ◽  
H E Yuan ◽  
A P Mitchell

Many yeast genes that are essential for meiosis are expressed only in meiotic cells. Known regulators of early meiotic genes include IME1, which is required for their expression, and SIN3 and UME6, which prevent their expression in nonmeiotic cells. We report here the molecular characterization of the RIM11 gene, which we find is required for expression of several early meiotic genes. A close functional relationship between RIM11 and IME1 is supported by two observations. First, sin3 and ume6 mutations are epistatic to rim11 mutations; prior studies have demonstrated their epistasis to ime1 mutations. Second, overexpression of RIM11 can suppress an ime1 missense mutation (ime1-L321F) but not an ime1 deletion. Sequence analysis indicates that RIM11 specifies a protein kinase related to rat glycogen synthase kinase 3 and the Drosophila shaggy/zw3 gene product. Three partially defective rim11 mutations alter residues involved in ATP binding or catalysis, and a completely defective rim11 mutation alters a tyrosine residue that corresponds to the site of an essential phosphorylation for glycogen synthase kinase 3. Immune complexes containing a hemagglutinin (HA) epitope-tagged RIM11 derivative, HA-RIM11, phosphorylate two proteins, p58 and p60, whose biological function is undetermined. In addition, HA-RIM11 immune complexes phosphorylate a functional IME1 derivative but not the corresponding ime1-L321F derivative. We propose that RIM11 stimulates meiotic gene expression through phosphorylation of IME1.


1997 ◽  
Vol 75 (6) ◽  
pp. 568-575 ◽  
Author(s):  
R Bouley ◽  
M Gosselin ◽  
H Plante ◽  
G Servant ◽  
J Pérodin ◽  
...  

FEBS Letters ◽  
1996 ◽  
Vol 387 (1) ◽  
pp. 75-77 ◽  
Author(s):  
Toru Nakano ◽  
Junji Kishino ◽  
Hitoshi Arita

2012 ◽  
Vol 52 (12) ◽  
pp. 3233-3244 ◽  
Author(s):  
Paola Bisignano ◽  
Chiara Lambruschini ◽  
Manuele Bicego ◽  
Vittorio Murino ◽  
Angelo D. Favia ◽  
...  

1987 ◽  
Vol 258 (2) ◽  
pp. 470-481 ◽  
Author(s):  
Mohammed G. Hegazy ◽  
Thomas J. Thysseril ◽  
Keith K. Schlender ◽  
Erwin M. Reimann

2006 ◽  
Vol 349 (4) ◽  
pp. 1206-1213 ◽  
Author(s):  
Marko Oblak ◽  
Simona Golič Grdadolnik ◽  
Miha Kotnik ◽  
Arnaud Poterszman ◽  
R. Andrew Atkinson ◽  
...  

2012 ◽  
Vol 32 (17) ◽  
pp. 3486-3499 ◽  
Author(s):  
P. Rada ◽  
A. I. Rojo ◽  
N. Evrard-Todeschi ◽  
N. G. Innamorato ◽  
A. Cotte ◽  
...  

2013 ◽  
Vol 13 (1) ◽  
pp. 64 ◽  
Author(s):  
Thomas Bittner ◽  
Sarah Campagne ◽  
Gunther Neuhaus ◽  
Stefan A Rensing ◽  
Christiane Fischer-Iglesias

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