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. 2019 Nov 7;10:5052. doi: 10.1038/s41467-019-12969-x

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Response of NPC1 variants to SAHA. a Schematic representation of domains in NPC1 (sterol-binding luminal N-terminal domain 1 (SNLD1), N-terminal transmembrane domain 2 (NTMD2), middle luminal domain 3 (MLD3), sterol-sensing transmembrane domain 4 (STMD4), C-terminal luminal domain 5 (CLD5), C-terminal transmembrane domain 6 (CTMD6)). b (Upper panel) Trafficking of NPC1 variants from the ER (Endo H sensitive (Endo H^S)) to post-ER LE/LY compartments (Endo H resistant (Endo H^R)) glycoforms in wild-type (WT) and NPC1 patient fibroblasts. (Bottom panel) Fraction of total of NPC1 in Endo H^R (black) and Endo H^S (white) glycoforms (mean ± s.d.). c NPC1 variants are mapped as balls on the C-alpha position in the NPC1 structure^25,29. The cholesterol molecule is shown in magenta^25,35. d (Left panel) Trafficking index (TrIdx) of 48 NPC1 variants in the absence (black circles as control (CTL)) or presence of SAHA (red squares). WT, I1061T variants are indicated by vertical dash lines and trafficking classes (II, III, IV) by horizontal dash lines. (Right panel) Cholesterol (Chol) homeostasis of 48 NPC1 variants in the absence (black circles as control (CTL)) or presence of SAHA (red squares for p-value < 0.05; blue squares for p-value > 0.05; student’s two tailed t-test)²¹. WT and I1061T variants are indicated by vertical dash lines. Chol of WT in the absence or presence of SAHA highlighted by horizontal dashed lines. Data are presented as mean ± s.e.m.²¹ (Source data are provided as a Source Data file). e Domain specific response to SAHA. NPC1 variants are clustered into different domains for TrIdx (left panel) and Chol (right panel) comparison (box and whisker plot: box = 25th and 75th, whiskers extend from minimum to maximum of the data; p-value (Student’s two tailed t-test)). f Correlation between TrIdx and Chol of NPC1 variants in the absence (left panel) or presence (right panel) of SAHA. Pearson’s r and the p-value (ANOVA test) with null hypothesis as the coefficient equal to zero is indicated. g Redistribution of different trafficking classes in response to SAHA. The percentage of variants in different classes in absence (f, left panel) or presence (f, right panel) of SAHA is shown