PubMed · 3094694
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W F Tucker, S MacNeil. 1986-10-04. Psoriasis.. https://doi.org/10.1136/bmj.293.6551.882-b
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Bridge-like lipid transfer proteins (BLTPs) play fundamental roles in cellular lipid redistribution between organellar membranes. They comprise bridge domains spanning organelles at contact sites that allow lipids to transit through the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables lipid transfer. To address the mechanisms underlying the assembly and regulation of BLTP complexes, we used cryo-EM to resolve the structure of one such BLTP, the Parkinson's disease protein VPS13C, at near-atomic resolution. The structure identifies a lipid-transfer-nonpermissive conformation, in which the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. We also identify calmodulin (CaM), central to calcium signaling, as a constitutive VPS13C interactor. Calcium induces conformational changes in the VPS13C-CaM complex, suggesting calcium regulation of VPS13 function. Altogether, this structure of intact VPS13C serves as a starting point for understanding its regulation and that of other VPS13 proteins.
Calmodulin (CaM) plays a central role in cardiac excitation-contraction coupling by regulating ion channels, including the L-type calcium (Ca2+) channel Cav1.2 and the voltage-gated potassium (K+) channel Kv7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca2+ binding at the C-terminal lobe of CaM, altering its Ca2+-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca2+-dependent inactivation (CDI) of Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, thereby limiting repolarising K+ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca2+ and K+ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability.
Tumor necrosis factor (TNF) is a 17-kDa protein produced by endotoxin-stimulated macrophages. We have demonstrated that recombinant human TNF activates human macrophages to kill intracellular bacteria of the Mycobacterium avium complex (MAC) in a dose-related manner. TNF also primed macrophages to produce superoxide anion (O2-) following treatment with phorbol esther PMA (0.1 micrograms/ml). To investigate the intracellular pathway involved in the TNF-mediated activation of mycobacteriostatic/mycobactericidal activity in macrophages, we used two different protein kinase C (PKC) inhibitors: H7 (10(-5)-10(7) M) and staurosporine (10(-7)-10(-9) M). Mellitin (1 and 100 mM) was used as a calmodulin inhibitor. Human peripheral blood-derived macrophages cultured for 7 days were treated with H7, mellitin, or staurosporine for 1 hr prior to incubation with TNF (10(3) U/ml). Twenty-four hours after treatment with TNF the O2- release was measured spectrophotometrically following exposure to PMA. Macrophages were infected with MAC and the viable intracellular bacilli were quantitated following 4 days of treatment with TNF. All PKC inhibitors suppressed O2- production after incubation with PMA. However, treatment with either PKC or calmodulin inhibitors did not influence the intracellular killing of M. avium by TNF-stimulated macrophages. Exposure of the macrophages to cGMP inhibitor but not to cAMP inhibitor significantly impaired the response to the stimulation with TNF. In contrast, incubation of macrophages with protein kinase A (PKA) had no effect on TNF-mediated mycobacteriostatic/mycobactericidal activity. These results suggest that the TNF-mediated mycobactericidal activity in cultured macrophages probably occurs by a PKC-independent mechanism.