title: Stereospecific gating of functional motions in Pin1.
abstract: Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide, and two pS-P substrate analogue inhibitors locked in the cis and trans conformations. Specifically, we compared the ligand binding modes and binding-induced changes in Pin1 side-chain flexibility. The cis and trans binding modes differ, and produce different mobility in Pin1. The cis-locked inhibitor and substrate produced a loss of side-chain flexibility along an internal conduit of conserved hydrophobic residues, connecting the domain interface with the isomerase active site. The trans-locked inhibitor produces a weaker conduit response. Thus, the conduit response is stereoselective. We further show interactions between the peptidyl-prolyl isomerase and Trp-Trp (WW) domains amplify the conduit response, and alter binding properties at the remote peptidyl-prolyl isomerase active site. These results suggest that specific input conformations can gate dynamic changes that support intraprotein communication. Such gating may help control the propagation of chemical signals by Pin1, and other modular signaling proteins.
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors: Andrew T
authors: AT
authors: Namanja
authors: Xiaodong J
authors: XJ
authors: Wang
authors: Bailing
authors: B
authors: Xu
authors: Ana Y
authors: AY
authors: Mercedes-Camacho
authors: Kimberly A
authors: KA
authors: Wilson
authors: Felicia A
authors: FA
authors: Etzkorn
authors: Jeffrey W
authors: JW
authors: Peng
mesh_terms: D020816:Amino Acid Motifs; D001667:Binding, Competitive; D055592:Biophysical Phenomena; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019906:Nuclear Magnetic Resonance, Biomolecular; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011994:Recombinant Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase