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| http://purl.uniprot.org/citations/20937381 | http://www.w3.org/2000/01/rdf-schema#comment | "The missense mutation pG46S in the regulatory (R) domain of human phenylalanine hydroxylase (hPAH), associated with a severe form of phenylketonuria, generates a misfolded protein which is rapidly degraded on expression in HEK293 cells. When overexpressed as a MBP-G46S fusion protein, soluble and fully active tetrameric/dimeric forms are assembled and recovered in a metastable conformational state. When MBP is cleaved off, G46S undergoes a conformational change and self-associates with a lag phase and an autocatalytic growth phase (tetramers≫dimers), as determined by light scattering. The self-association is controlled by pH, ionic strength, temperature, protein concentration and the phosphorylation state of Ser16; the net charge of the protein being a main modulator of the process. A superstoichiometric amount of WT dimers revealed a 2-fold enhancement of the rate of G46S dimer self-association. Electron microscopy demonstrates the formation of higher-order oligomers and linear polymers of variable length, partly as a branching network, and partly as individual long and twisted fibrils (diameter ~145-300Å). The heat-shock proteins Hsp70/Hsp40, Hsp90 and a proposed pharmacological PAH chaperone (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) partly inhibit the self-association process. Our data indicate that the G46S mutation results in a N-terminal extension of α-helix 1 which perturbs the wild-type α-β sandwich motif in the R-domain and promotes new intermolecular contacts, self-association and non-amyloid fibril formation. The metastable conformational state of G46S as a MBP fusion protein, and its self-association propensity when released from MBP, may represent a model system for the study of other hPAH missense mutations characterized by misfolded proteins."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.bbadis.2010.09.015"xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/author | "Leandro P."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/author | "Flatmark T."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/author | "Saraste J."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/author | "Leandro J."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/author | "Simonsen N."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/name | "Biochim Biophys Acta"xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/pages | "106-120"xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/title | "Phenylketonuria as a protein misfolding disease: The mutation pG46S in phenylalanine hydroxylase promotes self-association and fibril formation."xsd:string |
| http://purl.uniprot.org/citations/20937381 | http://purl.uniprot.org/core/volume | "1812"xsd:string |
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