Aβ cascade hypothesis being considered most evident event in AD pathology and even today it holds good. Dysregulation of catalytic events of Aβ regulating enzymes can possibly cause faulty Aβ trafficking; inequity of Aβ formation and clearance resulting in misfolded protein accumulation, neurodegeneration and cognitive impairment. Many novel approaches have been made on this pathway to discover new molecules, unfortunately couldn't reach the terminal phases of clinical trials. Over decades, studies have been more focused on enzyme chemistry and explored the relationship between structural features and catalytic function of Aβ regulating enzymes. However, the modulations of catalytic mechanisms of those enzymes have not been imposed so far to reduce the Aβ load. Hence, in this review, we have critically detailed the knowledge of basic structural dynamics and possible catalytic modulations of enzymes responsible for Aβ formation and clearance that will impart new perspectives in drug discovery process.
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http://dx.doi.org/10.1016/j.bbrc.2022.09.068 | DOI Listing |
Cell Rep
June 2019
Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK. Electronic address:
AAA+ proteins form asymmetric hexameric rings that hydrolyze ATP and thread substrate proteins through a central channel via mobile substrate-binding pore loops. Understanding how ATPase and threading activities are regulated and intertwined is key to understanding the AAA+ protein mechanism. We studied the disaggregase ClpB, which contains tandem ATPase domains (AAA1, AAA2) and shifts between low and high ATPase and threading activities.
View Article and Find Full Text PDFElife
November 2018
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
The biogenesis of 60S ribosomal subunits is initiated in the nucleus where rRNAs and proteins form pre-60S particles. These pre-60S particles mature by transiently interacting with various assembly factors. The ~5000 amino-acid AAA+ ATPase Rea1 (or Midasin) generates force to mechanically remove assembly factors from pre-60S particles, which promotes their export to the cytosol.
View Article and Find Full Text PDFJ Biol Chem
December 2018
From the Department of Biology, Faculty of Science and Engineering and
ClpB, a bacterial homologue of heat shock protein 104 (Hsp104), can disentangle aggregated proteins with the help of the DnaK, a bacterial Hsp70, and its co-factors. As a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA), ClpB forms a hexameric ring structure, with each protomer containing two AAA modules, AAA1 and AAA2. A long coiled-coil middle domain (MD) is present in the C-terminal region of the AAA1 and surrounds the main body of the ring.
View Article and Find Full Text PDFStructure
December 2018
Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA. Electronic address:
Cytoplasmic dynein, whose motor domain belongs to the AAA+ family, walks on microtubules toward the minus end. Using the available structures in different nucleotide states, we performed simulations of a coarse-grained model to elucidate the dynamics of allosteric transitions. Binding of ATP closes the cleft between the AAA1 and AAA2 domains, triggering conformational changes in the rest of the motor domain, thus forming the pre-power stroke state.
View Article and Find Full Text PDFFront Mol Biosci
February 2017
Center for Molecular Biology of the Heidelberg University, German Cancer Research Center Heidelberg, Germany.
The members of the hexameric AAA+ disaggregase of and , ClpB, and Hsp104, cooperate with the Hsp70 chaperone system in the solubilization of aggregated proteins. Aggregate solubilization relies on a substrate threading activity of ClpB/Hsp104 fueled by ATP hydrolysis in both ATPase rings (AAA-1, AAA-2). ClpB/Hsp104 ATPase activity is controlled by the M-domains, which associate to the AAA-1 ring to downregulate ATP hydrolysis.
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