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Glucokinase: from allosteric glucose sensing to disease variants.
Trends Biochem Sci
January 2025
Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, Denmark. Electronic address:
Human glucokinase (GCK) functions as a glucose sensor in the pancreas and liver, where GCK activity regulates insulin secretion and glycogen synthesis, respectively. GCK's low affinity for glucose and the sigmoidal substrate dependency of enzymatic turnover enables it to act as a sensor that makes cells responsive to changes in circulating glucose levels. Its unusual kinetic properties are intrinsically linked to the enzyme's conformational dynamics.
View Article and Find Full Text PDFMolecular basis of proton sensing by G protein-coupled receptors.
Cell
December 2024
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94148, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address:
Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Imperial College London, London, United Kingdom.
Background: Neuroinflammation is a key component of Alzheimer's Disease (AD) pathology. Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial to microglial involvement in AD, mediating trem2-dependent activation and Disease-Associated Microglia (DAM) polarization. However, GWAS revealed that loss-of-function mutations of its encoding gene are an important risk factor for AD.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Stanford University, School of Medicine, Stanford, CA, USA.
Background: Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta-amyloid and tau biomarkers can now add in-vivo support to the AD diagnosis.
View Article and Find Full Text PDFClinical Manifestations.
Alzheimers Dement
December 2024
Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Background: Neuropsychiatric symptoms (NPS) are common in early stages of Alzheimer's disease (AD) and may be early markers of cognitive decline and dementia in older individuals. The Mild Behavioral Impairment Checklist (MBI-C) was developed to capture new-onset transdiagnostic NPS in individuals at risk of dementia. We sought to determine whether mild behavioral impairment symptoms are elevated in non-demented Presenilin-1 (PSEN1) E280A carriers, who are genetically determined to develop dementia by their 50s.
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