title: Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1.
abstract: Pin1 is a modular peptidyl-prolyl isomerase specific for phosphorylated Ser/Thr-Pro (pS/T-P) motifs, typically within intrinsically disordered regions of signaling proteins. Pin1 consists of two flexibly linked domains: an N-terminal WW domain for substrate binding and a larger C-terminal peptidyl-prolyl isomerase (PPIase) domain. Previous studies showed that binding of phosphopeptide substrates to Pin1 could alter Pin1 interdomain contact, strengthening or weakening it depending on the substrate sequence. Thus, substrate-induced changes in interdomain contact may act as a trigger within the Pin1 mechanism. Here, we investigate this possibility via nuclear magnetic resonance studies of several Pin1 mutants. Our findings provide new mechanistic insights for those substrates that reduce interdomain contact. Specifically, the reduced interdomain contact can allosterically enhance PPIase activity relative to that when the contact is sustained. These findings suggest Pin1 interdomain contact can negatively regulate its activity.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Mahoney
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Zintsmaster
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, USA. Electronic address: jpeng@nd.edu.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Peng
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase