Caspase-6 is critical to the neurodegenerative pathways of Alzheimer's, Huntington's, and Parkinson's diseases and has been identified as a potential molecular target for treatment of neurodegeneration. Thus, understanding the global and regional changes in dynamics and conformation provides insights into the unique properties of caspase-6 that may contribute to achieving control of its function. In this work, hydrogen/deuterium exchange MS (H/DX-MS) was used to map the local changes in the conformational flexibility of procaspase-6 at the discrete states that reflect the series of cleavage events that ultimately lead to the fully active, substrate-bound state. Intramolecular self-cleavage at Asp-193 evoked higher solvent exposure in the regions of the substrate-binding loops L1, L3, and L4 and in the 130s region, the intersubunit linker region, the 26-32 region as well as in the stabilized loop 2. Additional removal of the linker allowed caspase-6 to gain more flexibility in the 130s region and in the L2 region converting caspase-6 to a competent substrate-binding state. The prodomain region was found to be intrinsically disordered independent of the activation state of caspase-6; however, its complete removal resulted in the protection of the adjacent 26-32 region, suggesting that this region may play a regulatory role. The molecular details of caspase-6 dynamics in solution provide a comprehensive scaffold for strategic design of therapeutic approaches for neurodegenerative disorders.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617271 | PMC |
http://dx.doi.org/10.1073/pnas.1704640114 | DOI Listing |
J Exp Bot
January 2025
Ministry of Education Key Laboratory of Molecular and Cellular Biology; Hebei Research Center of the Basic Discipline of Cell Biology; Hebei Collaboration Innovation Center for Cell Signaling and Environmental Adaptation; Hebei Key Laboratory of Molecular and Cellular Biology; College of Life Sciences, Hebei Normal University, 050024 Shijiazhuang, China.
A well-constructed pollen wall is essential for pollen fertility, which relies on the contribution of tapetum. Our results demonstrate an essential role of the tapetum-expressed protein phosphatase 2A (PP2A) B'α and B'β in pollen wall formation. The b'aβ double mutant pollen grains harbored sticky remnants and tectum breakages, resulting in failed release.
View Article and Find Full Text PDFMAGMA
January 2025
Aix Marseille Univ, CNRS, CRMBM, Marseille, France.
Objective: Segmentation of individual thigh muscles in MRI images is essential for monitoring neuromuscular diseases and quantifying relevant biomarkers such as fat fraction (FF). Deep learning approaches such as U-Net have demonstrated effectiveness in this field. However, the impact of reducing neural network complexity remains unexplored in the FF quantification in individual muscles.
View Article and Find Full Text PDFCurr Atheroscler Rep
January 2025
Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France.
Purpose Of Review: While lipid-lowering therapies demonstrate efficacy, many patients still contend with significant residual risk of atherosclerotic cardiovascular diseases (ASCVD). The intestine plays a pivotal role in regulating circulating lipoproteins levels, thereby exerting influence on ASCVD pathogenesis. This review underscores recent genetic findings from the last six years that delineate new biological pathways and actors in the intestine which regulate lipid-related ASCVD risk.
View Article and Find Full Text PDFMol Neurobiol
January 2025
Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China.
Dysregulation of long non-coding RNAs (lncRNAs) is implicated in the pathophysiology of ischemic stroke (IS). However, the molecular mechanism of the lncRNA SERPINB9P1 in IS remains unclear. Our study aimed to explore the role and molecular mechanism of the lncRNA SERPINB9P1 in IS.
View Article and Find Full Text PDFArch Orthop Trauma Surg
January 2025
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, 4710-057, Portugal.
Introduction: Total joint arthroplasties generally achieve good outcomes, but chronic pain and disability are a significant burden after these interventions. Acknowledging relevant risk factors can inform preventive strategies. This study aimed to identify chronic pain profiles 6 months after arthroplasty using the ICD-11 (International Classification of Diseases) classification and to find pre and postsurgical predictors of these profiles.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!