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Susan S. Taylor, Friedrich W Herberg, Gianluigi Veglia, Jian Wu
First published: 28 February 2023
Although Fischer’s extraordinary career came to focus mostly on the protein phosphatases, after his co-discovery of Phosphorylase Kinase with Ed Krebs he was clearly intrigued not only by cAMP-dependent protein kinase (PKA), but also by the heat-stable, high-affinity protein kinase inhibitor (PKI). PKI is an intrinsically disordered protein that contains at its N-terminus a pseudo-substrate motif that binds synergistically and with high-affinity to the PKA catalytic (C) subunit. The sequencing and characterization of this inhibitor peptide (IP20) were validated by the structure of the PKA C-subunit solved first as a binary complex with IP20 and then as a ternary complex with ATP and two magnesium ions. A second motif, nuclear export signal (NES), was later discovered in PKI. Both motifs correspond to amphipathic helices that convey high-affinity binding. The dynamic features of full-length PKI, recently captured by NMR, confirmed that the IP20 motif becomes dynamically and sequentially ordered only in the presence of the C-subunit. The type I PKA regulatory (R) subunits also contain a pseudo-substrate ATPMg2-dependent high-affinity inhibitor sequence. PKI and PKA, especially the Cβ subunit, are highly expressed in the brain, and PKI expression is also cell cycle-dependent. In addition, PKI is now linked to several cancers. The full biological importance of PKI and PKA signaling in the brain, and their importance in cancer thus remains to be elucidated.
Elyse S. Fischer
First published: 14 December 2022
The spindle assembly checkpoint (SAC) is a cellular surveillance mechanism that functions to ensure accurate chromosome segregation during mitosis. Macromolecular complexes known as kinetochores, act as the interface of sister chromatid attachment to spindle microtubules. In response to unattached kinetochores, the SAC activates its effector, the mitotic checkpoint complex (MCC), which delays mitotic exit until all sister chromatid pairs have achieved successful attachment to the bipolar mitotic spindle. Formation of the MCC (composed of Mad2, BubR1, Bub3 and Cdc20) is regulated by an Mps1 kinase-dependent phosphorylation signaling cascade which assembles and repositions components of the MCC onto a catalytic scaffold. This scaffold functions to catalyze the conversion of the HORMA-domain protein Mad2 from an “inactive” open-state (O-Mad2) into an “active” closed-Mad2 (C-Mad2), and simultaneous Cdc20 binding. Here, our current understanding of the molecular mechanisms underlying the kinetic barrier to C-Mad2:Cdc20 formation will be reviewed. Recent progress in elucidating the precise molecular choreography orchestrated by the catalytic scaffold to rapidly assemble the MCC will be examined, and unresolved questions will be highlighted. Ultimately, understanding how the SAC rapidly activates the checkpoint not only provides insights into how cells maintain genomic integrity during mitosis, but also provides a paradigm for how cells can utilize molecular switches, including other HORMA domain-containing proteins, to make rapid changes to a cell’s physiological state.
Cândida Dias, Eliana Fernandes, Rui M. Barbosa, João Laranjinha, Ana Ledo
First published: 17 April 2023
Under physiological conditions, the energetic demand of the brain is met by glucose oxidation. However, ample evidence suggests that lactate produced by astrocytes through aerobic glycolysis may also be an oxidative fuel, highlighting the metabolic compartmentalization between neural cells. Herein, we investigate the roles of glucose and lactate in oxidative metabolism in hippocampal slices, a model that preserves neuron–glia interactions. To this purpose, we used high-resolution respirometry to measure oxygen consumption (O2 flux) at the whole tissue level and amperometric lactate microbiosensors to evaluate the concentration dynamics of extracellular lactate. We found that lactate is produced from glucose and transported to the extracellular space by neural cells in hippocampal tissue. Under resting conditions, endogenous lactate was used by neurons to support oxidative metabolism, which was boosted by exogenously added lactate even in the presence of excess glucose. Depolarization of hippocampal tissue with high K+ significantly increased the rate of oxidative phosphorylation, which was accompanied by a transient decrease in extracellular lactate concentration. Both effects were reverted by inhibition of the neuronal lactate transporter, monocarboxylate transporters 2 (MCT2), supporting the concept of an inward flux of lactate to neurons to fuel oxidative metabolism. We conclude that astrocytes are the main source of extracellular lactate which is used by neurons to fuel oxidative metabolism, both under resting and stimulated conditions.
Biotechnology and Applied Biochemistry
Rippin, Anil K. Sharma, Vikas Beniwal
First published: 25 March 2023
Condensed and hydrolyzable tannins are secondary metabolites present in almost every plant part. Tannase enzyme acts on hydrolyzable tannins to produce gallic acid and tannase-mediated end-products with immense therapeutic potential. Seven different fruits with significant presence of hydrolyzable tannin content were selected to check for phenol, tannin, and hydrolyzable tannin contents. Prunus domestica had the maximum phenol content, that is, 85.4 ± 0.207, followed by Syzygium cumini, Fragaria ananassa, Rubus fruticosus, and Psidium guajava. Plum showed the maximum number of hydrolyzable tannins. Fruit extracts were subjected to tannase hydrolysis and their antimicrobial and antioxidant activities were determined. There was a significant increase in the antioxidant abilities of the fruits with Punica granatum extract, displaying the highest decline of 132 units of IC50 followed by F. ananassa hydrolyzable extract, showing a decrease from 224.75 to 119.98 μg/mL. The extracts also depicted a significant increase in antibacterial activity after hydrolysis against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus with Rubus idaeus aqueous extract observed to be most effective against E. coli. The increase in antioxidant and antibacterial activity can be attributed to the production of tannase-mediated products formed after the biotransformation of hydrolyzable tannins present in the aqueous extracts.
Biochemistry and Molecular Biology Education
Swati Agrawal, Shane Austin
First published: 06 April 2023
We present here two accessible ways for enhanced understanding of complex biological structures and their function in undergraduate Biology and Biochemistry classrooms. These methods can be applied for in-class instruction as well as for remote lessons, as they are cheap, easily available and easy to implement. LEGO® bricks and MERGE CUBE based augmented reality can be applied to make three-dimensional representation for any structure available on PDB. We envisage these techniques to be useful for students when visualizing simple stereochemical problems or complex pathway interactions.
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Molecular Aspects of Medicine
Volume 91 (June 2023) 101151
Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics
by Yash Gupta a, Oleksandr V. Savytskyi b f, Matt Coban b d, Amoghavarsha Venugopal a, Vasili Pleqi a, Caleb A. Weber b, Rohit Chitale a e, Ravi Durvasula a, Christopher Hopkins f, Prakasha Kempaiah a, Thomas R. Caulfield b c g h i
Aspects of Molecular Medicine
Volume 1 (2023) 100008
sgRNAs: A SARS-CoV-2 emerging issue
by Antonio Mori Antonio Mori 1, Denise Lavezzari 1, Elena Pomari, Michela Deiana, Chiara Piubelli, Maria Rosaria Capobianchi, Concetta Castilletti
If you are interested in reviewing for Aspects of Molecular Medicine, or would like to apply to be an Editorial Board Member, visit our journal homepage to find out more.