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Insight into vitamin B6 -dependent epilepsy due to PLPBP (previously PROSC) missense mutations

AuthorsTremino-Agulló, Lorena ; Forcada-Nadal, Alicia ; Rubio, Vicente
KeywordsCOG0325 family proteins
PLPBP gene
PLPHP characterization
PLPHP recombinant production
Inborn errors
pyridoxal phosphate
Site-directed mutagenesis
Structure-function correlations
Issue DateJul-2018
CitationHuman Mutation 39(7):1002-1013 (2018)
AbstractVitamin B6 -dependent genetic epilepsy was recently associated to mutations in PLPBP (previously PROSC), the human version of the widespread COG0325 gene that encodes TIM-barrel-like pyridoxal phosphate (PLP)-containing proteins of unclear function. We produced recombinantly, purified and characterized human PROSC (called now PLPHP) and its six missense mutants reported in epileptic patients. Normal PLPHP is largely a monomer with PLP bound through a Schiff-base linkage. The PLP-targeting antibiotic d-cycloserine decreased the PLP-bound peak as expected for pseudo-first-order reaction. The p.Leu175Pro mutation grossly misfolded PLPHP. Mutations p.Arg241Gln and p.Pro87Leu decreased protein solubility and yield of pure PLPHP, but their pure forms were well folded, similarly to pure p.Pro40Leu, p.Tyr69Cys, and p.Arg205Gln mutants (judged from CD spectra). PLPHP stability was decreased in p.Arg241Gln, p.Pro40Leu, and p.Arg205Gln mutants (thermofluor assays). The p.Arg241Gln and p.Tyr69Cys mutants respectively lacked PLP or had a decreased amount of this cofactor. With p.Tyr69Cys there was extensive protein dimerization due to disulfide bridge formation, and PLP accessibility was decreased (judged from d-cycloserine reaction). A 3-D model of human PLPHP allowed rationalizing the effects of most mutations. Overall, the six missense mutations caused ill effects and five of them impaired folding or decreased stability, suggesting the potential of pharmacochaperone-based therapeutic approaches.
Description12 páginas, 3 figuras, 2 tablas. "This is the pre-peer reviewed version of the following article: Hum Mutat. 2018 Jul;39(7):1002-1013, which has been published in final form at http://dx.doi.org/10.1002/humu.23540. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."
Publisher version (URL)http://dx.doi.org/10.1002/humu.23540
Appears in Collections:(IBV) Artículos
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