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    • The protein kinase CK mediated phosphorylation

    2024-04-16

    The protein kinase CK2-mediated phosphorylation of HMGN1 was implicated to be involved in age-associated amnesia in rats [31]. It was shown that the decreased level of HMGN1 phosphorylation due to the down-regulation of CK2 activity could cause amnesia in aged rats, whereas the treatment with protein kinase CK2 activator could partially relieve the symptom [31], highlighting the importance of CK2-mediated phosphorylation in the physiological functions of HMGN1. We believe that the identification of new sites of phosphorylation in human HMGN1 catalyzed by protein kinase CK2 may facilitate the future examination of the biological functions of the HMGN1 protein.
    Acknowledgment
    Introduction Mitochondria are the centre of metabolism in cells, coupling the oxidation of substrates to ATP synthesis by an electrochemical proton gradient. Varying this protonmotive force allows for adjustments in energy metabolism to maintain metabolic homeostasis. For this reason, the coupling of substrate oxidation is incomplete, as protons can leak across the mitochondrial inner membrane independently of ATP production. This unregulated futile proton conductance is of considerable physiological relevance, as it can account for as much as 20–70% of cellular metabolic rate depending on cell type [1], [2]. A majority of proton leak can be strictly attributed to the abundance, but not activity, of mitochondrial carrier proteins such as the Protease Inhibitor Cocktail (EDTA-Free, 100X in DMSO) sale nucleotide translocase (ANT) and, in brown adipose tissue (BAT), uncoupling protein 1 (UCP1) [3], [4]. Importantly, the regulation of proton leak allows for responses to fluctuations in energy demands and controls energy transduction to maintain cellular homeostasis and body function. The first proton leak mechanism was identified in BAT, where UCP1-catalysed proton conductance generates heat to defend body temperature during cold acclimation [5]. Sequence similarity allowed the identification of its paralogous proteins UCP2 and UCP3 [6], [7]. These UCPs do not contribute to basal proton conductance in vitro in the absence of specific activators [8]. When activated, however, all UCPs (including avian and plant UCPs) can catalyse proton leak [9]. The precise mechanisms of activation and inhibition of both UCP2 and UCP3, as well as their physiological role, remain uncertain [10], [11]. There has been considerable recent progress, however, in understanding the transcriptional and translational regulation that implicates UCP2 and UCP3 in adaptation to nutritional status and oxidative stress. More recently, the unique dynamic regulation of UCP2 reveals a new mechanism for the regulation of mitochondrial energy metabolism by the novel UCPs.
    Acute activation of uncoupling protein activity UCP1 activity is highly regulated at the molecular level by small molecules. It is inhibited by physiological concentrations of purine nucleoside di- and tri-phosphates and stimulated when fatty acids overcome nucleotide inhibition [12]. How fatty acids activate the net protonophoric activity of UCP1 is still debated. Broadly, there are three models that can explain the dependence on fatty acids. In the first, fatty acids act as co-factors by embedding their carboxyl groups in the core of the protein to bind and release protons as they access amino acid side chains during transport [13]. Evidence that UCP1 can translocate chloride and fatty acid anions suggests a second model. In this mechanism, protonated fatty acids freely diffuse across the mitochondrial inner membrane. The pH gradient promotes their dissociation into fatty acid anions in the matrix, and the fatty acid anions are then exported from the matrix by UCP1 [14]. The net activity results in proton conductance across the inner membrane, though in this model UCP1 itself does not translocate protons. Thirdly, fatty acids themselves may not be directly required for UCP1 activity, but instead act as allosteric activators by promoting a conformation of the protein that is protonophoric (or that translocates hydroxide ions), since fatty acids and nucleotides appear to affect proton conductance in a manner described by simple competitive kinetics [15], [16].