title: The acidic pH-induced structural changes in Pin1 as revealed by spectral methodologies.
abstract: Pin1 is closely associated with the pathogenesis of cancers and Alzheimer's disease (AD). Previously, we have shown the characteristics of the thermal denaturation of Pin1. Herein, the acid-induced denaturation of Pin1 was determined by means of fluorescence emission, synchronous fluorescence, far-UV CD, ANS fluorescence and RLS spectroscopies. The fluorescence emission spectra and the synchronous fluorescence spectra suggested the partially reversible unfolding (approximately from pH 7.0 to 4.0) and refolding (approximately from pH 4.0 to 1.0) of the structures around the chromophores in Pin1, apparently with an intermediate state at about pH 4.0-4.5. The far-UV CD spectra indicated that acidic pH (below pH 4.0) induced the structural transition from α-helix and random coils to β-sheet in Pin1. The ANS fluorescence and the RLS spectra further suggested the exposure of the hydrophobic side-chains of Pin1 and the aggregation of it especially below pH 2.3, and the aggregation possibly resulted in the formation of extra intermolecular β-sheet. The present work primarily shows that acidic pH can induce kinds of irreversible structural changes in Pin1, such as the exposure of the hydrophobic side-chains, the transition from α-helix to β-sheet and the aggregation of Pin1, and also explains why Pin1 loses most of its activity below pH 5.0. The results emphasize the important role of decreased pH in the pathogenesis of some Pin1-related diseases, and support the therapeutic approach for them by targeting acidosis and modifying the intracellular pH gradients.
authors.affiliation: Key Laboratory of Bio-resources and Eco-environment of the Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, PR China.
authors.forename: Jing-Zhang
authors.initials: JZ
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.forename: Guo-Fei
authors.initials: GF
authors.lastname: Zhu
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Han
authors.forename: Yue
authors.initials: Y
authors.lastname: Luo
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Lin-Fang
authors.initials: LF
authors.lastname: Du
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry*; D011489:Protein Denaturation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase