title: Transient domain interactions enhance the affinity of the mitotic regulator Pin1 toward phosphorylated peptide ligands.
abstract: The mitotic regulator Pin1 plays an important role in protein quality control and age-related medical conditions such as Alzheimer disease and Parkinson disease. Although its cellular role has been thoroughly investigated during the past decade, the molecular mechanisms underlying its function remain elusive. We provide evidence for interactions between the two domains of Pin1. Several residues displayed unequivocal peak splits in nuclear magnetic resonance spectra, indicative of two different conformational states in equilibrium. Pareto analysis of paramagnetic relaxation enhancement data demonstrates that the two domains approach each other upon addition of a nonpeptidic ligand. Titration experiments with phosphorylated peptides monitored by fluorescence anisotropy and chemical shift perturbation indicate that domain interactions increase Pin1's affinity toward peptide ligands. We propose this interplay of the domains and ligands to be a general mechanism for a large class of two-domain proteins.
authors: Research Group Structural and Medicinal Biochemistry, ZMB, University of Duisburg-Essen, 45117 Essen, Germany.
authors: Anja
authors: A
authors: Matena
authors: Christian
authors: C
authors: Sinnen
authors: Johannes
authors: J
authors: van den Boom
authors: Christoph
authors: C
authors: Wilms
authors: J Nikolaj
authors: JN
authors: Dybowski
authors: Ricarda
authors: R
authors: Maltaner
authors: Jonathan W
authors: JW
authors: Mueller
authors: Nina M
authors: NM
authors: Link
authors: Daniel
authors: D
authors: Hoffmann
authors: Peter
authors: P
authors: Bayer
mesh_terms: D005454:Fluorescence Polarization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019906:Nuclear Magnetic Resonance, Biomolecular; D019696:Peptidylprolyl Isomerase / Q000737:chemistry*; D010748:Phosphopeptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D012996:Solutions; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D008024:Ligands; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010748:Phosphopeptides; D012996:Solutions; D012997:Solvents; D011092:Polyethylene Glycols; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase