Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB Predict Disease Progression and Monitor Treatment Response.
The authors demonstrate that lysobisphosphatidic acid enrichment in human NPC2-deficient cells either directly or via its biosynthetic precursor phosphtidylglycerol (PG) is entirely ineffective indicating an obligate functional interaction between NPC2 and lysobisphosphatidic acid in cholesterol trafficking.
conclude that NPC2's affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein.
Results propose that depending on the location of the cholesterol ligand a dynamical interface between the NPC2 and NPC1 N-terminal domain (NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).
Data show that nuclear factor kappa B subunit 2 (NF-kappaB2) regulates intracellular cholesterol transport by controlling Niemann Pick type C2 protein (NPC2) expression.
Overall we provide a mechanism by which npc2-mediated cholesterol transport is controlled by the membrane composition and how npc2-lipid interactions can regulate the transport rate.
New variant associated with Niemann-Pick disease type C: Neurological manifestations and biochemical molecular and cellular characterisation." trans "Nueva variante asociada a enfermedad de Niemann-Pick tipo C: manifestaciones neurologicas y caracterizacion bioquimica molecular y celular.
Study demonstrates that Niemann-Pick type C disease can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomegaly due to mutation in NPC2 gene.
Docking of the NPC1-NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and N-terminal domain cholesterol binding pockets supporting the "hydrophobic hand-off" cholesterol transfer model.
suggest a general mechanism for NPC2 mediated sterol transfer in which Phe66 Val96 and Tyr100 act as reversible gate keepers. These residues stabilize the sterol in the binding pose via pi-pi stacking but move transiently apart during sterol release
Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophagy mitochondrial quality control and mitochondrial function.
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