The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production

Abstract

Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-beta peptides (Abeta) derived from amyloid precursor protein (APP), but their exact relationship remains elusive. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Abeta production in vitro. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase. Pin1 has been proposed to regulate protein function by accelerating conformational changes, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease. However, the role of Pin1 in APP processing and Abeta production is unknown. Here we show that Pin1 has profound effects on APP processing and Abeta production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces Abeta secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Abeta42 (a major toxic species) in brains in an age-dependent manner, with Abeta42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Abeta production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

Peptidyl-prolyl isomerization targets rice Aux/IAAs for proteasomal degradation during auxin signalling

“…The ratios of cross to diagonal peak intensities for cis and trans conformations in the ROESY spectra were dependent on the total exchange rate constant k ex of a two-state exchange process (cis2trans) and the mixing time of the ROESY experiments (t m ). The exchange rate constants were obtained by fitting one of the following equations using different ratios with different mixing times 59,60 :…”

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

“…A recent work provided a possible link between Thr 668 phosphorylation and APP processing through the prolyl isomerase Pin1. The authors showed that Pin1 binds to the phosphorylated Thr 668 -Pro motif and promotes the isomerization of the proline residue (85). This leads to a conformational change of the APP intracellular domain and alteration of APP processing and Aβ production.…”

NMR reveals novel mechanisms of protein activity regulation

“…Proline cis-trans isomerization has emerged as a particularly efficient regulatory mechanism in many biological processes, including cell signaling, [62][63][64][65] neurodegeneration, 66 amyloidogenesis, 67 channel gating, 68 gene regulation, 69,70 phage and virus infection, 71,72 enzyme function, 73,74 and ligand recognition. 75 Proline isomerization is unique in that it exerts its function through multiple mechanisms involving (i) significant conformational changes caused by the 180 rotation about the prolyl bond, (ii) slow kinetics of isomerization affording a molecular timer, and (iii) the recruitment of prolyl cis-trans isomerase enzymes (PPIases).…”