Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia. Electronic address:
Published: July 2022
AI Article Synopsis
Article Abstract
The multifunctional AAA+ ATPase p97 is an unfoldase/segregase involved in various cellular processes and present in all kingdoms of life. In mammals and yeast, p97 functions upstream of the proteasome. Interestingly, proteasome inhibitors targeting pathogenic microorganisms display efficacy in overcoming drug-resistant strains. Homologues of p97 have been found in disease-causing parasites and mycobacteria. Here, we review the current knowledge on the structure, function, and conservation of p97 in pathogens. We discuss the potential of parasite and mycobacterial p97 as a drug target against these pathogens and explore strategies in designing novel inhibitors. A successful strategy for inhibiting pathogenic p97 should lead to effectively killing the pathogen, minimising toxic and off-target effects, and providing specificity to avoid interfering with human p97.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disease characterized by symptoms like ataxia, dementia, and epilepsy, caused by an expansion of CAG repeats in the ATROPHIN 1 (ATN1) gene.
Researchers developed Drosophila (fruit fly) models that express either normal ATN1 (Q7) or a pathogenic version with expanded repeats (Q88), revealing that the pathogenic variant significantly reduces fly motility, lifespan, and affects internal structures more severely than the normal version.
RNA sequencing identified pathways related to protein quality control that are altered by pathogenic ATN1, and subsequent genetic experiments highlighted the
The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations in and disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is the PEX1 allele, which results in a reduction of peroxisomal protein import.
WD repeat domain 74 (WDR74) is a nucleolar protein involved in the early stages of pre-60S maturation in the ribosome biogenesis pathway. In later stages, WDR74 interacts with MTR4, an RNA helicase that functions with the exosome nuclease complex, and is dissociated upon ATP hydrolysis by the chaperone-like nuclear VCP-like 2 (NVL2) AAA-ATPase. We previously reported that ATP hydrolysis-defective NVL2 causes aberrant accumulation of WDR74 on the MTR4-exosome complex at the nucleolar periphery and in the nucleoplasm and that this nuclear redistribution of WDR74 leads to the unusual cleavage of the early rRNA precursor within the internal transcribed spacer 1 sequence.
The recent development of the DNA-binding domain (DBD)-dynein chimera motors with a dynein motor core and a DNA-binding domain has made it possible to move on DNA nanostructure tracks. In contrast to naturally occurring cytoskeletal filaments such as microtubules and actin filaments, DNA tracks can be programmed with structural properties such as length, stiffness, and circumference. There might be many advantages to using DNA as a track, for example, for applications in nanotechnology.
Cadmium (Cd) is a major soil pollutant that threatens plant growth and human health. The plant ATPase associated with various cellular activities (AAA) SKD1 utilizes ATP hydrolysis energy to mediate cellular responses to environmental stress. However, the role and regulatory mechanisms of SKD1 in plant responses to Cd stress are not well understood.
