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provides coniferyl ferulate(CAS#:29623-29-8) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of coniferyl ferulate are included as well.>> amp version: coniferyl ferulate
Gephyrin and collybistin are key components of GABAA receptor (GABAAR) clustering. Nonetheless, resolving the molecular interactions between the plethora of GABAAR subunits and these clustering proteins is a significant challenge. We report a direct interaction of GABAAR α2 and α3 subunit intracellular M3-M4 domain (but not α1, α4, α5, α6, β1-3, or γ1-3) with gephyrin. Curiously, GABAAR α2, but not α3, binds to both gephyrin and collybistin using overlapping sites. The reciprocal binding sites on gephyrin for collybistin and GABAAR α2 also overlap at the start of the gephyrin E domain. This suggests that although GABAAR α3 interacts with gephyrin, GABAAR α2, collybistin, and gephyrin form a trimeric complex. In support of this proposal, tri-hybrid interactions between GABAAR α2 and collybistin or GABAAR α2 and gephyrin are strengthened in the presence of gephyrin or collybistin, respectively. Collybistin and gephyrin also compete for binding to GABAAR α2 in co-immunoprecipitation experiments and co-localize in transfected cells in both intracellular and submembrane aggregates. Interestingly, GABAAR α2 is capable of “activating ” collybistin isoforms harboring the regulatory SH3 domain, enabling targeting of gephyrin to the submembrane aggregates. The GABAAR α2-collybistin interaction was disrupted by a pathogenic mutation in the collybistin SH3 domain (p.G55A) that causes X-linked intellectual disability and seizures by disrupting GABAAR and gephyrin clustering. Because immunohistochemistry in retina revealed a preferential co-localization of collybistin with α2 subunit containing GABAARs, but not GlyRs or other GABAAR subtypes, we propose that the collybistin-gephyrin complex has an intimate role in the clustering of GABAARs containing the α2 subunit.
GABA Receptors, Genetic Diseases, Neuroscience, Protein Targeting, Synapses, Collybistin, GABAAR α2, Gephyrin, Synaptic Clustering, Yeast Tri-hybrid Interactions
Complex Role of Collybistin and Gephyrin in GABAA Receptor Clustering*An external file that holds a picture, illustration, etc. Object name is sbox.jpg
Leila Saiepour,‡,1,2 Celine Fuchs,‡,1 Annarita Patrizi,§ Marco Sassoe-Pognetto,§ Robert J. Harvey,‡ and Kirsten Harvey‡,3
2010 Sep 17;
More than 80% of the rate acceleration for enzymatic catalysis of the aldose-ketose isomerization of (R)-glyceraldehyde 3-phosphate (GAP) by triosephosphate isomerase (TIM) can be attributed to the 3′-phosphodianion group of GAP. We examine here the necessity of the covalent connection between the phosphodianion and triose sugar portions of the substrate by “carving up” GAP into the minimal neutral two-carbon sugar glycolaldehyde and phosphite dianion pieces. This “two-part substrate” preserves both the α-hydroxycarbonyl and oxydianion portions of GAP. TIM catalyzes proton transfer from glycolaldehyde in D2O, resulting in deuterium incorporation that can be monitored by 1H NMR spectroscopy, with kcat/Km = 0.26 M-1 s-1. Exogenous phosphite dianion results in a very large increase in the observed second-order rate constant (kcat/Km)obsd for turnover of glycolaldehyde, and the dependence of (kcat/Km)obsd on [HPO32-] exhibits saturation. The data give kcat/Km = 185 M-1s-1 for turnover of glycolaldehyde by TIM that is saturated with phosphite dianion, so that the separate binding of phosphite dianion to TIM results in a 700-fold acceleration of proton transfer from carbon. The binding of phosphite dianion to the free enzyme (Kd = 38 mM) is 700-fold weaker than its binding to the fleeting complex of TIM with the altered substrate in the transition state (Kd‡ = 53 μM); the total intrinsic binding energy of phosphite dianion in the transition state is 5.8 kcal/mol. We propose a physical model for catalysis by TIM in which the intrinsic binding energy of the substrate phosphodianion group is utilized to drive closing of the “mobile loop” and a protein conformational change that leads to formation of an active site environment that is optimally organized for stabilization of the transition state for proton transfer from α-carbonyl carbon.
Enzymatic Catalysis of Proton Transfer at Carbon Activation of Triosephosphate Isomerase by Phosphite Dianion†
Tina L. Amyes and John P. Richard‡
2008 Oct 1.
Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR-196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo. Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC.
miR-196b-5p, cancer stem cell, chemotherapeutic resistance, STAT3 signaling pathway, CRC
Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway
Dong Ren,#1,2 Bihua Lin,#1 Xin Zhang,1,3 Yao Peng,4 Ziyu Ye,1 Yan Ma,1 Yangfang Liang,5 Longbin Cao,4 Xiangyong Li,1 Ronggang Li,3 Lixia Sun,3 Qiongru Liu,3 Jinhua Wu,6 Keyuan Zhou,1 and Jincheng Zeng1
2017 Jul 25;