Annexin 3 (ANX A3) represents approximately 1% of the total protein of human neutrophils and promotes tight contact between membranes of isolated specific granules in vitro leading to their aggregation. Like for other annexins, the primary molecular events of the action of this protein is likely its binding to negatively charged phospholipid membranes in a Ca(2+)-dependent manner, via Ca(2+)-binding sites located on the convex side of the highly conserved core of the molecule. The conformation and dynamics of domain III can be affected by this process, as it was shown for other members of the family. The 20 amino-acid, N-terminal segment of the protein also could be affected and also might play a role in the modulation of its binding to the membranes. The structure and dynamics of these two regions were investigated by fluorescence of the two tryptophan residues of the protein (respectively, W190 in domain III and W5 in the N-terminal segment) in the wild type and in single-tryptophan mutants. By contrast to ANX A5, which shows a closed conformation and a buried W187 residue in the absence of Ca(2+), domain III of ANX A3 exhibits an open conformation and a widely solvent-accessible W190 residue in the same conditions. This is in agreement with the three-dimensional structure of the ANX A3-E231A mutant lacking the bidentate Ca(2+) ligand in domain III. Ca(2+) in the millimolar concentration range provokes nevertheless a large mobility increase of the W190 residue, while interaction with the membranes reduces it slightly. In the N-terminal region, the W5 residue, inserted in the central pore of the protein, is weakly accessible to the solvent and less mobile than W190. Its amplitude of rotation increases upon binding of Ca(2+) and returns to its original value when interacting with membranes. Ca(2+) concentration for half binding of the W5A mutant to negatively charged membranes is approximately 0.5 mM while it increases to approximately 1 mM for the ANX A3 wild type and to approximately 3 mM for the W190 ANX A3 mutant. In addition to the expected perturbation of the W190 environment at the contact surface between the protein and the membrane bilayer, binding of the protein to Ca(2+) and to membranes modulates the flexibility of the ANX A3 hinge region at the opposite of this interface and might affect its membrane permeabilizing properties.
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http://dx.doi.org/10.1110/ps.4230102 | DOI Listing |
J Med Syst
January 2025
Computer Science Institute, DISIT, University of Eastern Piedmont, Alessandria, Italy.
In traditional medical education, learners are mostly trained to diagnose and treat patients through supervised practice. Artificial Intelligence and simulation techniques can complement such an educational practice. In this paper, we present GLARE-Edu, an innovative system in which AI knowledge-based methodologies and simulation are exploited to train learners "how to act" on patients based on the evidence-based best practices provided by clinical practice guidelines.
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Neuroimage Analytics Laboratory and Glenn Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX, USA.
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Alzheimers Dement
December 2024
Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
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View Article and Find Full Text PDFAlzheimers Dement
December 2024
Neuropsychology and Clinical Neuroscience Laboratory (LANNEC), Physiopathology Department - ICBM, Neuroscience and East Neuroscience Departments, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Background: The Alzheimer's Disease (AD) continuum is composed of Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and Alzheimer's Disease Dementia (ADD). Changes in grey matter volume (GMV), characteristic of the AD continuum, are related to cognitive and activities of daily living (ADL) impairments. ADLs are divided into three domains: i) Basic (BADL), ii) Instrumental (IADL), and iii) Advanced (AADL), and their study is critical for understanding the evolution and adequate follow-up of patients.
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