FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2896901256> ?p ?o ?g. }

• W2896901256 abstract "ABSTRACT Genetic diversity provides a rich repository for understanding the role of proteostasis in the management of the protein fold to allow biology to evolve through variation in the population and in response to the environment. Failure in proteostasis can trigger multiple disease states affecting both human health and lifespan. Niemann-Pick C (NPC) disease is a genetic disorder mainly caused by mutations in NPC1, a multi-spanning transmembrane protein that is trafficked through the exocytic pathway to late endosomes and lysosomes (LE/Ly) to manage cholesterol homeostasis. Proteostatic defects triggered by >600 NPC1 variants found in the human population inhibit export of NPC1 protein from ER or function in downstream LE/Ly, leading to accumulation of cholesterol and rapid onset neurodegeneration in childhood for most patients. We now show that chemical allosteric inhibitors, such as JG98, targeting the cytosolic Hsp70 chaperone/co-chaperone complex improves the trafficking and stability of NPC1 variants with diverse NPC1 genotypes. By exploiting the knowledge-base of NPC1 variants found in the world-wide patient population using Variation Spatial Profiling (VSP), a Gaussian-process based machine learning (ML) approach, we show how the Hsp70 chaperone system alters the spatial covariance (SCV) tolerance of the ER and the SCV set-points for each residue of the NPC1 polypeptide chain differentially to improve trafficking efficiency and post-ER stability for variants distributed across the entire NPC1 polypeptide. The impact of JG98 is supported by the observation that silencing of Hsp70 specific nucleotide exchange factors (NEF) (BCL-anthogene (BAG) family) co-chaperones significantly improve the folding status of NPC1 variants. Together, these studies suggest that targeting the cytosolic Hsp70 system to adjust the SCV tolerance of the proteostasis network can improve recognition of the plasticity of the NPC1 fold found in the disease population for trafficking to the LE/Ly compartments." @default.
• W2896901256 created "2018-10-26" @default.
• W2896901256 creator A5018655786 @default.
• W2896901256 creator A5024971176 @default.
• W2896901256 creator A5030048603 @default.
• W2896901256 creator A5038953566 @default.
• W2896901256 creator A5040066574 @default.
• W2896901256 creator A5056722454 @default.
• W2896901256 creator A5059429574 @default.
• W2896901256 date "2018-10-09" @default.
• W2896901256 modified "2023-10-16" @default.
• W2896901256 title "Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System" @default.
• W2896901256 cites W1492302030 @default.
• W2896901256 cites W1496815279 @default.
• W2896901256 cites W1623462303 @default.
• W2896901256 cites W1873149227 @default.
• W2896901256 cites W1971805725 @default.
• W2896901256 cites W1978837079 @default.
• W2896901256 cites W1979229843 @default.
• W2896901256 cites W1980020885 @default.
• W2896901256 cites W1980087135 @default.
• W2896901256 cites W1983606596 @default.
• W2896901256 cites W199204758 @default.
• W2896901256 cites W2026324678 @default.
• W2896901256 cites W2026717899 @default.
• W2896901256 cites W2045077644 @default.
• W2896901256 cites W2056911532 @default.
• W2896901256 cites W2061062422 @default.
• W2896901256 cites W2068262899 @default.
• W2896901256 cites W2073761443 @default.
• W2896901256 cites W2076159058 @default.
• W2896901256 cites W2078741614 @default.
• W2896901256 cites W2080261305 @default.
• W2896901256 cites W2103865125 @default.
• W2896901256 cites W2112374700 @default.
• W2896901256 cites W2126528483 @default.
• W2896901256 cites W2130392121 @default.
• W2896901256 cites W2132617605 @default.
• W2896901256 cites W2152231829 @default.
• W2896901256 cites W2153074213 @default.
• W2896901256 cites W2162066969 @default.
• W2896901256 cites W2163739062 @default.
• W2896901256 cites W2169228158 @default.
• W2896901256 cites W2169409747 @default.
• W2896901256 cites W2171260748 @default.
• W2896901256 cites W2290533065 @default.
• W2896901256 cites W2327844212 @default.
• W2896901256 cites W2345399459 @default.
• W2896901256 cites W2396636851 @default.
• W2896901256 cites W2439567776 @default.
• W2896901256 cites W2463412817 @default.
• W2896901256 cites W2471059767 @default.
• W2896901256 cites W2473711714 @default.
• W2896901256 cites W2478642516 @default.
• W2896901256 cites W2490327928 @default.
• W2896901256 cites W2499006706 @default.
• W2896901256 cites W2507716909 @default.
• W2896901256 cites W2513570588 @default.
• W2896901256 cites W2538913332 @default.
• W2896901256 cites W2573232933 @default.
• W2896901256 cites W2590982773 @default.
• W2896901256 cites W2595886211 @default.
• W2896901256 cites W2606353566 @default.
• W2896901256 cites W2615550277 @default.
• W2896901256 cites W2707292079 @default.
• W2896901256 cites W2744732181 @default.
• W2896901256 cites W2747962007 @default.
• W2896901256 cites W2751896753 @default.
• W2896901256 cites W2769205163 @default.
• W2896901256 cites W2770026599 @default.
• W2896901256 cites W2774357023 @default.
• W2896901256 cites W2792640665 @default.
• W2896901256 cites W2810892605 @default.
• W2896901256 cites W2839995495 @default.
• W2896901256 cites W2852209137 @default.
• W2896901256 cites W2885799426 @default.
• W2896901256 cites W2887996376 @default.
• W2896901256 cites W2952207682 @default.
• W2896901256 doi "https://doi.org/10.1101/437764" @default.
• W2896901256 hasPublicationYear "2018" @default.
• W2896901256 type Work @default.
• W2896901256 sameAs 2896901256 @default.
• W2896901256 citedByCount "1" @default.
• W2896901256 countsByYear W28969012562019 @default.
• W2896901256 crossrefType "posted-content" @default.
• W2896901256 hasAuthorship W2896901256A5018655786 @default.
• W2896901256 hasAuthorship W2896901256A5024971176 @default.
• W2896901256 hasAuthorship W2896901256A5030048603 @default.
• W2896901256 hasAuthorship W2896901256A5038953566 @default.
• W2896901256 hasAuthorship W2896901256A5040066574 @default.
• W2896901256 hasAuthorship W2896901256A5056722454 @default.
• W2896901256 hasAuthorship W2896901256A5059429574 @default.
• W2896901256 hasBestOaLocation W28969012561 @default.
• W2896901256 hasConcept C102747710 @default.
• W2896901256 hasConcept C142724271 @default.
• W2896901256 hasConcept C2775962898 @default.
• W2896901256 hasConcept C2778552423 @default.
• W2896901256 hasConcept C2781452922 @default.
• W2896901256 hasConcept C2908647359 @default.
• W2896901256 hasConcept C54355233 @default.

• next