Transglutaminase inhibition stimulates hematopoiesis and reduces aggressive behavior of crayfish, Pacifastacus leniusculus [Cell Biology]

November 13th, 2018 by Kingkamon Junkunlo, Kenneth Soderhall, Irene Soderhall

Transglutaminase (TGase) is a Ca2+-dependent cross-linking enzyme, which has both enzymatic and non-enzymatic properties. TGase is involved in several cellular activities, including adhesion, migration, survival, apoptosis, and extracellular matrix (ECM) organization. In this study, we focused on the role of the TGase enzyme in controlling hematopoiesis in the crayfish Pacifastacus leniusculus. We hypothesized that a high TGase activity could mediate an interaction of progenitor cells with the ECM to maintain cells in an undifferentiated stage in the hematopoietic tissue (HPT). We found here that the reversible inhibitor cystamine decreases the enzymatic activity of TGase from crayfish HPT as well as from guinea pig in a concentration-dependent manner. Cystamine injection could decrease TGase activity in HPT without affecting production of reactive oxygen species (ROS). Moreover the decrease in TGase activity in the HPT increased the number of circulating hemocytes. Interestingly the cystamine-mediated TGase inhibition reduced aggressive behavior and movement in crayfish. In conclusion, we show that cystamine-mediated TGase inhibition directly releases HPT progenitor cells from the HPT into the peripheral circulation in the hemolymph and strongly reduces aggressive behavior in crayfish.

Exploring the quinone/inhibitor-binding pocket in mitochondrial respiratory complex I by chemical biology approaches [Enzymology]

November 13th, 2018 by Shinpei Uno, Hironori Kimura, Masatoshi Murai, Hideto Miyoshi

NADH-quinone oxidoreductase (respiratory complex I) couples NADH-to-quinone electron transfer to the translocation of protons across the membrane. Even though the architectures of the quinone-access channel in the enzyme have been modeled by X-ray crystallography and cryo-EM, conflicting findings raise the question whether the models fully reflect physiologically relevant states present throughout the catalytic cycle. To gain further insights into the structural features of the binding pocket for quinone/inhibitor, we performed chemical biology experiments using bovine heart sub-mitochondrial particles. We synthesized ubiquinones that are oversized (SF-UQs) or lipid-like (PC-UQs) and are highly unlikely to enter and transit the predicted narrow channel. We found that SF-UQs and PC-UQs can be catalytically reduced by complex I, albeit only at moderate or low rates. Moreover, quinone-site inhibitors completely blocked the catalytic reduction and the membrane potential formation coupled to this reduction. Photoaffinity-labeling experiments revealed that amiloride-type inhibitors bind to the interfacial domain of multiple core subunits (49 kDa, ND1, and PSST) and 39 kDa supernumerary subunit, although the latter does not make up the channel cavity in the current models. The binding of amilorides to the multiple target subunits was remarkably suppressed by other quinone-site inhibitors and SF-UQs. Taken together, the present results are difficult to reconcile with the current channel models. On the basis of comprehensive interpretations of the present results and of previous findings, we discuss the physiological relevance of these models.

HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity

November 5th, 2018 by Huanbin Wang

HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity

HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity, Published online: 05 November 2018; doi:10.1038/s41589-018-0161-x

HIP1R directly interacts with PD-L1 and targets PD-L1 for lysosomal degradation. Development of a rationally designed peptide incorporating the PD-L1 binding sequence of HIP1R with a lysosomal targeting sequence promotes PD-L1 degradation.
  • Posted in Nat Chem Biol, Publications
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[ASAP] In Situ Photoregulation of Carbonic Anhydrase Activity Using Azobenzenesulfonamides

October 31st, 2018 by Kanchan Aggarwal, Mandira Banik, Brenda Medellin, Emily L. Que

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Biochemistry
DOI: 10.1021/acs.biochem.8b00947

Small heat shock proteins: Simplicity meets complexity [Cell Biology]

October 31st, 2018 by Martin Haslbeck, Sevil Weinkauf, Johannes Buchner

Small heat shock proteins (sHsps) are a ubiquitous and ancient family of ATP-independent molecular chaperones. A key characteristic of sHsps is that they exist in ensembles of iso-energetic oligomeric species differing in size. This property arises from a unique mode of assembly involving several parts of the subunits in a flexible manner. Current evidence suggests that smaller oligomers are more active chaperones. Thus, a shift in the equilibrium of the sHsp ensemble allows regulating the chaperone activity. Different mechanisms have been identified that reversibly change the oligomer equilibrium. The promiscuous interaction with non-native proteins generates complexes that can form aggregate-like structures from which native proteins are restored by ATP-dependent chaperones such as Hsp70 family members. In recent years, this basic paradigm has been expanded and new roles, new cofactors as well as variations in structure and regulation of sHsps have emerged.

[ASAP] Precise Small Molecule Degradation of a Noncoding RNA Identifies Cellular Binding Sites and Modulates an Oncogenic Phenotype

October 29th, 2018 by Yue Li, Matthew D. Disney

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ACS Chemical Biology
DOI: 10.1021/acschembio.8b00827
  • Posted in ACS Chemical Biology, Publications
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Identification of a cellularly active SIRT6 allosteric activator

October 29th, 2018 by Zhimin Huang

Identification of a cellularly active SIRT6 allosteric activator

Identification of a cellularly active SIRT6 allosteric activator, Published online: 29 October 2018; doi:10.1038/s41589-018-0150-0

The use of an allosteric drug-design method resulted in the identification of a first-in-class cellularly active SIRT6 activator that induces cell-cycle arrest in the G0–G1 phase, thus suppressing proliferation in human hepatocellular carcinoma cells.

Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking

October 29th, 2018 by Xin Li

Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking

Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking, Published online: 29 October 2018; doi:10.1038/s41589-018-0144-y

An inhibitor of the YEATS domain was developed by targeting a unique π-π-π stacking in the YEATS–Kcr recognition. An ENL YEATS-selective inhibitor, XL-13m, helps probe the YEATS-dependent role of ENL in the leukemogenic transcription program.
  • Posted in Nat Chem Biol, Publications
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The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite

October 29th, 2018 by Iria Bernhardsgrütter

The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite

The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite, Published online: 29 October 2018; doi:10.1038/s41589-018-0153-x

Structural and biochemical analysis of propionyl-CoA synthase reveals that it forms a reaction chamber containing three active sites, which sequesters the reactive intermediate acrylyl-CoA during the conversion of 3-hydroxypropionate to propionyl-CoA.
  • Posted in Nat Chem Biol, Publications
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[ASAP] Retroelement-Based Genome Editing and Evolution

October 25th, 2018 by Anna J. Simon, Barrett R. Morrow, Andrew D. Ellington

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.8b00273