FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2023283451> ?p ?o ?g. }

• W2023283451 endingPage "33755" @default.
• W2023283451 startingPage "33745" @default.
• W2023283451 abstract "The proprotein convertase PCSK9 is a major target in the treatment of hypercholesterolemia because of its ability bind the LDL receptor (LDLR) and enhance its degradation in endosomes/lysosomes. In the endoplasmic reticulum, the zymogen pro-PCSK9 is first autocatalytically cleaved at its internal Gln152↓, resulting in a secreted enzymatically inactive complex of PCSK9 with its inhibitory prosegment (prosegment·PCSK9), which is the active form of PCSK9 on the LDLR. We mutagenized the P1 cleavage site Gln152 into all other residues except Cys and analyzed the expression and secretion of the resulting mutants. The data demonstrated the following. 1) The only P1 residues recognized by PCSK9 are Gln > Met > Ala > Ser > Thr ≈ Asn, revealing an unsuspected specificity. 2) All other mutations led to the formation of an unprocessed zymogen that acted as a dominant negative retaining the native protein in the endoplasmic reticulum. Analysis of a large panoply of known natural and artificial point mutants revealed that this general dominant negative observation applies to all PCSK9 mutations that result in the inability of the protein to exit the endoplasmic reticulum. Such a tight quality control property of the endoplasmic reticulum may lead to the development of specific PCSK9 small molecule inhibitors that block its autocatalytic processing. Finally, inspired by the most active gain-of-function mutant, D374Y, we evaluated the LDLR degradation activity of 18 Asp374 variants of PCSK9. All Asp374 mutations resulted in similar gain-of-function activity on the LDLR except that D374E was as active as native PCSK9, D374G was relatively less active, and D374N and D374P were completely inactive. The proprotein convertase PCSK9 is a major target in the treatment of hypercholesterolemia because of its ability bind the LDL receptor (LDLR) and enhance its degradation in endosomes/lysosomes. In the endoplasmic reticulum, the zymogen pro-PCSK9 is first autocatalytically cleaved at its internal Gln152↓, resulting in a secreted enzymatically inactive complex of PCSK9 with its inhibitory prosegment (prosegment·PCSK9), which is the active form of PCSK9 on the LDLR. We mutagenized the P1 cleavage site Gln152 into all other residues except Cys and analyzed the expression and secretion of the resulting mutants. The data demonstrated the following. 1) The only P1 residues recognized by PCSK9 are Gln > Met > Ala > Ser > Thr ≈ Asn, revealing an unsuspected specificity. 2) All other mutations led to the formation of an unprocessed zymogen that acted as a dominant negative retaining the native protein in the endoplasmic reticulum. Analysis of a large panoply of known natural and artificial point mutants revealed that this general dominant negative observation applies to all PCSK9 mutations that result in the inability of the protein to exit the endoplasmic reticulum. Such a tight quality control property of the endoplasmic reticulum may lead to the development of specific PCSK9 small molecule inhibitors that block its autocatalytic processing. Finally, inspired by the most active gain-of-function mutant, D374Y, we evaluated the LDLR degradation activity of 18 Asp374 variants of PCSK9. All Asp374 mutations resulted in similar gain-of-function activity on the LDLR except that D374E was as active as native PCSK9, D374G was relatively less active, and D374N and D374P were completely inactive." @default.
• W2023283451 created "2016-06-24" @default.
• W2023283451 creator A5009035456 @default.
• W2023283451 creator A5016179057 @default.
• W2023283451 creator A5065470757 @default.
• W2023283451 creator A5090995081 @default.
• W2023283451 date "2012-09-01" @default.
• W2023283451 modified "2023-10-02" @default.
• W2023283451 title "Loss- and Gain-of-function PCSK9 Variants" @default.
• W2023283451 cites W1965676778 @default.
• W2023283451 cites W1968953041 @default.
• W2023283451 cites W1970090817 @default.
• W2023283451 cites W1986040042 @default.
• W2023283451 cites W1989730880 @default.
• W2023283451 cites W2006562777 @default.
• W2023283451 cites W2010689685 @default.
• W2023283451 cites W2011484220 @default.
• W2023283451 cites W2026136832 @default.
• W2023283451 cites W2028682402 @default.
• W2023283451 cites W2029753295 @default.
• W2023283451 cites W2034060255 @default.
• W2023283451 cites W2034844930 @default.
• W2023283451 cites W2034993121 @default.
• W2023283451 cites W2038614269 @default.
• W2023283451 cites W2040252771 @default.
• W2023283451 cites W2040612932 @default.
• W2023283451 cites W2046707901 @default.
• W2023283451 cites W2047861227 @default.
• W2023283451 cites W2048846412 @default.
• W2023283451 cites W2050348933 @default.
• W2023283451 cites W2055059015 @default.
• W2023283451 cites W2055571770 @default.
• W2023283451 cites W2056411372 @default.
• W2023283451 cites W2059210927 @default.
• W2023283451 cites W2062062360 @default.
• W2023283451 cites W2064207731 @default.
• W2023283451 cites W2064994526 @default.
• W2023283451 cites W2069993714 @default.
• W2023283451 cites W2073465333 @default.
• W2023283451 cites W2076648603 @default.
• W2023283451 cites W2076695593 @default.
• W2023283451 cites W2078669364 @default.
• W2023283451 cites W2087384149 @default.
• W2023283451 cites W2094108957 @default.
• W2023283451 cites W2094222285 @default.
• W2023283451 cites W2099136586 @default.
• W2023283451 cites W2101979622 @default.
• W2023283451 cites W2103606790 @default.
• W2023283451 cites W2110124859 @default.
• W2023283451 cites W2116970126 @default.
• W2023283451 cites W2117011155 @default.
• W2023283451 cites W2117109115 @default.
• W2023283451 cites W2118868005 @default.
• W2023283451 cites W2122864632 @default.
• W2023283451 cites W2136034547 @default.
• W2023283451 cites W2138457930 @default.
• W2023283451 cites W2140622082 @default.
• W2023283451 cites W2146660254 @default.
• W2023283451 cites W2159466552 @default.
• W2023283451 cites W2187330675 @default.
• W2023283451 cites W2330813682 @default.
• W2023283451 cites W2399446721 @default.
• W2023283451 doi "https://doi.org/10.1074/jbc.m112.399725" @default.
• W2023283451 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3460471" @default.
• W2023283451 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22875854" @default.
• W2023283451 hasPublicationYear "2012" @default.
• W2023283451 type Work @default.
• W2023283451 sameAs 2023283451 @default.
• W2023283451 citedByCount "70" @default.
• W2023283451 countsByYear W20232834512013 @default.
• W2023283451 countsByYear W20232834512014 @default.
• W2023283451 countsByYear W20232834512015 @default.
• W2023283451 countsByYear W20232834512016 @default.
• W2023283451 countsByYear W20232834512017 @default.
• W2023283451 countsByYear W20232834512018 @default.
• W2023283451 countsByYear W20232834512019 @default.
• W2023283451 countsByYear W20232834512020 @default.
• W2023283451 countsByYear W20232834512021 @default.
• W2023283451 countsByYear W20232834512022 @default.
• W2023283451 countsByYear W20232834512023 @default.
• W2023283451 crossrefType "journal-article" @default.
• W2023283451 hasAuthorship W2023283451A5009035456 @default.
• W2023283451 hasAuthorship W2023283451A5016179057 @default.
• W2023283451 hasAuthorship W2023283451A5065470757 @default.
• W2023283451 hasAuthorship W2023283451A5090995081 @default.
• W2023283451 hasBestOaLocation W20232834511 @default.
• W2023283451 hasConcept C102747710 @default.
• W2023283451 hasConcept C104317684 @default.
• W2023283451 hasConcept C143065580 @default.
• W2023283451 hasConcept C158617107 @default.
• W2023283451 hasConcept C170493617 @default.
• W2023283451 hasConcept C181199279 @default.
• W2023283451 hasConcept C185592680 @default.
• W2023283451 hasConcept C2778043179 @default.
• W2023283451 hasConcept C2778163477 @default.
• W2023283451 hasConcept C2778775115 @default.
• W2023283451 hasConcept C2778824825 @default.
• W2023283451 hasConcept C2780072125 @default.

• next