The classical view of protein function based on rigid, well-defined structures is being redefined by the emerging concept of intrinsic disorder. Conditionally disordered proteins (CDPs) repres Show more
The classical view of protein function based on rigid, well-defined structures is being redefined by the emerging concept of intrinsic disorder. Conditionally disordered proteins (CDPs) represent a subset of cellular intrinsically disordered proteins (IDPs) that transition between ordered and disordered states in response to specific stimuli, such as redox changes, post-translational modifications, ligand binding, interaction with partners, or environmental stress. This review explores the diverse landscape of conditional disorder and encompasses cryptic or dormant disordered regions, redox-sensitive motifs, metamorphic proteins, and proteins exhibiting order–disorder–new order transitions. These dynamic transitions allow CDPs to perform specialized regulatory, signalling, and stress-responsive roles, which often act as interaction hubs in complex cellular networks. Importantly, conditional disorder is not an anomaly but a conserved and functionally relevant feature across many proteomes. We highlight mechanistic insights into disorder-to-order transitions and their implications for cellular plasticity, adaptability, and disease. We also discuss how the conformational heterogeneity of CDPs complicates structure-based drug design, while offering unique therapeutic opportunities. Future directions include the integration of advanced biophysical techniques, computational modelling, and profiling to map, characterize, and target CDPs with greater precision. Overall, understanding the molecular logics of the conditional disorder will open new frontiers in structural biology and offer a deeper appreciation of protein versatility beyond static structural paradigms.
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The brain’s high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformatio Show more
The brain’s high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer’s disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential. Show less