Binary Complex
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Author(s):  
Kaushik Bhattacharya ◽  
Didier Picard

AbstractThe Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate (“client”) transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.


2021 ◽  
pp. 104359
Author(s):  
Yanfei Li ◽  
Tong Geng ◽  
Ang Li ◽  
Huimin Yu

2021 ◽  
Author(s):  
Hongwu Peng ◽  
Shanglin Zhou ◽  
Scott Weitze ◽  
Jiaxin Li ◽  
Sahidul Islam ◽  
...  

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nandan Haloi ◽  
Po-Chao Wen ◽  
Qunli Cheng ◽  
Meiying Yang ◽  
Gayathri Natarajan ◽  
...  

AbstractComplex formation between hexokinase-II (HKII) and the mitochondrial VDAC1 is crucial to cell growth and survival. We hypothesize that HKII first inserts into the outer membrane of mitochondria (OMM) and then interacts with VDAC1 on the cytosolic leaflet of OMM to form a binary complex. To systematically investigate this process, we devised a hybrid approach. First, we describe membrane binding of HKII with molecular dynamics (MD) simulations employing a membrane mimetic model with enhanced lipid diffusion capturing membrane insertion of its H-anchor. The insertion depth of the H-anchor was then used to derive positional restraints in subsequent millisecond-scale Brownian dynamics (BD) simulations to preserve the membrane-bound pose of HKII during the formation of the HKII/VDAC1 binary complex. Multiple BD-derived structural models for the complex were further refined and their structural stability probed with additional MD simulations, resulting in one stable complex. A major feature in the complex is the partial (not complete) blockade of VDAC1’s permeation pathway, a result supported by our comparative electrophysiological measurements of the channel in the presence and absence of HKII. We also show how VDAC1 phosphorylation disrupts HKII binding, a feature that is verified by our electrophysiology recordings and has implications in mitochondria-mediated cell death.


2021 ◽  
Vol 2021 (1) ◽  
pp. 44-51
Author(s):  
Adilya Jeyhun Ragimova ◽  
Vusala Ismayil Mardanova ◽  
Abel Maharram Maharramov ◽  
Khalil Jamal Nagiyev ◽  
Famil Musa Chyragov

The article considers the interaction of Ti(IV) with 2, 3, 4-trihydroxy-3'-fluoroazobenzene (H3R) in the presence and absence of phenontroline (Phen), α, α'-dipyridine (α, α'-dip), and batophenontroline (B-phen) studied by using a spectrophotometric method. It has been found that the yield of the binary complex is maximum at pHopt = 5 (λmax = 428 nm), and for mixed-ligand complexes, pHopt = 3.0; 4.0; 3.5; λmax = 477 nm, 443 nm, 440 nm Ti(OH)2(H2R)-Phen, Ti (OH)2(H2R)-α, α'-dip and Ti(OH)2(H2R)-B-phen, respectively. It has been investigated that a twofold excess of the reagent is required for complete binding of titanium(IV) into the complex. The influence of time and temperature on the complexation is investigated. The stability constants of binary and mixed-ligand titanium(IV) complexes were calculated: logβ = 8.61 ± 0.05 for Ti(OH)2(H2R)2, logβ = 10.98 ± 0.06 for Ti(OH)2(H2R)-Phen, logβ = 10.85 ± 0.04 for Ti (OH)2(H2R)-α, α'-dip, logβ = 11.26 ± 0.03 for Ti(OH)2(H2R)-B-phen. The ratio of the reacting components in the binary complex is 1 : 2, and in the mixed ligands 1 : 2 : 2. The influence of foreign ions and masking substances on the titanium(IV) complexation with reagents has been studied. The determination is practically not interfered by alkaline, alkaline-earth and some transition elements. Due to these characteristics, the complexes can be used for defining titanium(IV) in different objects.


2021 ◽  
pp. 111250
Author(s):  
Yundan Ruan ◽  
Pritam Guha ◽  
Shun-Li Chen ◽  
Qunhui Yuan ◽  
Wei Gan

2021 ◽  
Vol 26 (4) ◽  
pp. 547-559
Author(s):  
Ellen F. Vieux ◽  
Roman V. Agafonov ◽  
Lydia Emerson ◽  
Marta Isasa ◽  
Richard W. Deibler ◽  
...  

Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin–proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.


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