title: Peptide binding induces large scale changes in inter-domain mobility in human Pin1.
abstract: Pin1 is a peptidyl-prolyl cis/trans isomerase (PPIase) essential for cell cycle regulation. Pin1-catalyzed peptidyl-prolyl isomerization provides a key conformational switch to activate phosphorylation sites with the common phospho-Ser/Thr-Pro sequence motif. This motif is ubiquitously exploited in cellular response to a variety of signals. Pin1 is able to bind phospho-Ser/Thr-Pro-containing sequences at two different sites that compete for the same substrate. One binding site is located within the N-terminal WW domain, which is essential for protein targeting and localization. The other binding site is located in the C-terminal catalytic domain, which is structural homologous to the FK506-binding protein (FKBP) class of PPIases. A flexible linker of 12 residues connects the WW and catalytic domain. To characterize the structure and dynamics of full-length Pin1 in solution, high resolution NMR methods have been used to map the nature of interactions between the two domains of Pin1. In addition, the influence of target peptides on domain interactions has been investigated. The studies reveal a dynamic picture of the domain interactions. 15N spin relaxation data, differential chemical shift mapping, and residual dipolar coupling data indicate that Pin1 can either behave as two independent domains connected by the flexible linker or as a single intact domain with some amount of hinge bending motion depending on the sequence of the bound peptide. The functional importance of the modulation of relative domain flexibility in light of the multitude of interaction partners of Pin1 is discussed.
authors.affiliation: Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität Frankfurt, Marie-Curie Strasse 11, 60439 Frankfurt, Germany. d.jacobs@nmr.uni-frankfurt.de
authors.forename: Doris M
authors.initials: DM
authors.lastname: Jacobs
authors.forename: Krishna
authors.initials: K
authors.lastname: Saxena
authors.forename: Martin
authors.initials: M
authors.lastname: Vogtherr
authors.forename: Pau
authors.initials: P
authors.lastname: Bernado
authors.forename: Miquel
authors.initials: M
authors.lastname: Pons
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Fiebig
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D020134:Catalytic Domain; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010455:Peptides / Q000737:chemistry*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010455:Peptides; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase