000046937 001__ 46937
000046937 005__ 20210121114514.0
000046937 0247_ $$2doi$$a10.1371/journal.pone.0132141
000046937 0248_ $$2sideral$$a93347
000046937 037__ $$aART-2015-93347
000046937 041__ $$aeng
000046937 100__ $$0(orcid)0000-0002-8784-7735$$aMartínez-Oliván, J.
000046937 245__ $$aIntradomain confinement of disulfides in the folding of two consecutive modules of the LDL receptor
000046937 260__ $$c2015
000046937 5060_ $$aAccess copy available to the general public$$fUnrestricted
000046937 5203_ $$aThe LDL receptor internalizes circulating LDL and VLDL particles for degradation. Its extracellular binding domain contains ten (seven LA and three EGF) cysteine-rich modules, each bearing three disulfide bonds. Despite the enormous number of disulfide combinations possible, LDLR oxidative folding leads to a single native species with 30 unique intradomain disulfides. Previous folding studies of the LDLR have shown that non native disulfides are initially formed that lead to compact species. Accordingly, the folding of the LDLR has been described as a "coordinated nonvectorial" reaction, and it has been proposed that early compaction funnels the reaction toward the native structure. Here we analyze the oxidative folding of LA4 and LA5, the modules critical for ApoE binding, isolated and in the LA45 tandem. Compared to LA5, LA4 folding is slow and inefficient, resembling that of LA5 disease-linked mutants. Without Ca++, it leads to a mixture of many two-disulfide scrambled species and, with Ca++, to the native form plus two three-disulfide intermediates. The folding of the LA45 tandem seems to recapitulate that of the individual repeats. Importantly, although the folding of the LA45 tandem takes place through formation of scrambled isomers, no interdomain disulfides are detected, i.e. the two adjacent modules fold independently without the assistance of interdomain covalent interactions. Reduction of incredibly large disulfide combinatorial spaces, such as that in the LDLR, by intradomain confinement of disulfide bond formation might be also essential for the efficient folding of other homologous disulfide-rich receptors.
000046937 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P$$9info:eu-repo/grantAgreement/ES/MICINN/BFU2013-44763-P$$9info:eu-repo/grantAgreement/ES/MICINN/BFU2010-14901$$9info:eu-repo/grantAgreement/ES/DGA/PI078-08
000046937 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000046937 590__ $$a3.057$$b2015
000046937 591__ $$aMULTIDISCIPLINARY SCIENCES$$b11 / 62 = 0.177$$c2015$$dQ1$$eT1
000046937 592__ $$a1.427$$b2015
000046937 593__ $$aAgricultural and Biological Sciences (miscellaneous)$$c2015$$dQ1
000046937 593__ $$aMedicine (miscellaneous)$$c2015$$dQ1
000046937 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2015$$dQ1
000046937 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000046937 700__ $$aFraga, H.
000046937 700__ $$aArias-Moreno, X.
000046937 700__ $$aVentura, S.
000046937 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, J.$$uUniversidad de Zaragoza
000046937 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000046937 773__ $$g10, 7 (2015), 0132141 [17 p]$$pPLoS One$$tPloS one$$x1932-6203
000046937 8564_ $$s1747067$$uhttps://zaguan.unizar.es/record/46937/files/texto_completo.pdf$$yVersión publicada
000046937 8564_ $$s100981$$uhttps://zaguan.unizar.es/record/46937/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000046937 909CO $$ooai:zaguan.unizar.es:46937$$particulos$$pdriver
000046937 951__ $$a2021-01-21-10:58:53
000046937 980__ $$aARTICLE