Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1

Wang, Xinsheng; Mahoney, Brendan J.; Zhang, Meiling; Zintsmaster, John S.; Peng, Jeffrey W.

doi:10.1016/j.str.2015.08.019

Cited by 34 publications

(85 citation statements)

References 59 publications

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“…Strikingly, the linear relationship that we observe for the A140 and L141 peaks when isolated PPIase domain is apo, saturated with p131, or saturated with p144 (Fig. A) is consistent with the linear alignment observed for these same peaks in intact Pin1, Pin1‐I28A, Pin1W34A, and Pin1 saturated with pCdc25C peptide . The persistence of these linear trajectories of interface residue peaks observed here in the PPIase domain is fully consistent with the detailed and robust work that describes the role of these residues in intradomain and interdomain allostery in intact Pin1 .…”

Section: Resultssupporting

confidence: 88%

“…A) is consistent with the linear alignment observed for these same peaks in intact Pin1, Pin1‐I28A, Pin1W34A, and Pin1 saturated with pCdc25C peptide . The persistence of these linear trajectories of interface residue peaks observed here in the PPIase domain is fully consistent with the detailed and robust work that describes the role of these residues in intradomain and interdomain allostery in intact Pin1 . Our observation that binding of p131 to the WW domain is stronger in Pin1‐FL suggests that the dynamic PPIase conduit might positively regulate this interaction.…”

Section: Resultssupporting

confidence: 87%

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Neighboring phosphoSer‐Pro motifs in the undefined domain of IRAK1 impart bivalent advantage for Pin1 binding

et al. 2016

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The peptidyl prolyl isomerase Pin1 has two domains that are considered to be its binding (WW) and catalytic (PPIase) domains, both of which interact with phosphorylated Ser/Thr-Pro motifs. This shared specificity might influence substrate selection, since many known Pin1 substrates have multiple sequentially close phosphoSer/Thr-Pro motifs, including the protein IRAK1. The IRAK1 undefined domain (UD) contains two sets of such neighboring motifs (Ser131/Ser144 and Ser163/Ser173), suggesting possible bivalent interactions with Pin1. Using a series of NMR titrations with 15N-labeled full-length Pin1 (Pin1-FL), PPIase, or WW domain and phosphopeptides representing the Ser131/Ser144 and Ser163/Ser173 regions of IRAK1-UD, bivalent interactions were investigated. Binding studies using singly-phosphorylated peptides showed that individual motifs displayed weak affinities (>100 μM) for Pin1-FL and each isolated domain. Analysis of dually phosphorylated peptides binding to Pin1-FL showed that inclusion of bivalent states was necessary to fit the data. The resulting complex model and fitted parameters were applied to predict the impact of bivalent states at low micromolar concentrations, demonstrating significant affinity enhancement for both dually phosphorylated peptides (3.5 μM and 24 μM for peptides based on the Ser131/Ser144 and Ser163/Ser173 regions, respectively). The complementary technique biolayer interferometry confirmed the predicted affinity enhancement for a representative set of singly and dually phosphorylated Ser131/Ser144 peptides at low micromolar concentrations, validating model predictions. These studies provide novel insights regarding the complexity of interactions between Pin1 and activated IRAK1, and more broadly suggest that phosphorylation of neighboring Ser/Thr-Pro motifs in proteins might provide competitive advantage at cellular concentrations for engaging with Pin1.

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Section: Resultssupporting

confidence: 88%

Section: Resultssupporting

confidence: 87%

Neighboring phosphoSer‐Pro motifs in the undefined domain of IRAK1 impart bivalent advantage for Pin1 binding

et al. 2016

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“…74–76 Third, NMR studies showed that binding of both substrates and a nonpeptidic ligand (polyethylene glycol) to the WW domain resulted in tighter coupling between the two domains. 77–78 The allosteric communication in Pin1 has been investigated in recent studies based on NMR spectroscopy 26,79–81 and molecular dynamics simulations. 37,82 …”

Section: Case Studies Of Dynamic Effects In Allosteric Regulationmentioning

confidence: 99%

“…Recent CPMD RD data provided validation of reduced exchange dynamics upon binding Cdc25C and were interpreted as reflecting weakened interdomain contact. 81 …”

Section: Case Studies Of Dynamic Effects In Allosteric Regulationmentioning

confidence: 99%

Protein Allostery and Conformational Dynamics

2016

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The functions of many proteins are regulated through allostery, whereby effector binding at a distal site changes the functional activity (e.g., substrate binding affinity or catalytic efficiency) at the active site. Most allosteric studies have focused on thermodynamic properties, in particular, substrate binding affinity. Changes in substrate binding affinity by allosteric effectors have generally been thought to be mediated by conformational transitions of the proteins, or alternatively, by changes in the broadness of the free energy basin of the protein conformational state without shifting the basin minimum position. When effector binding changes the free energy landscape of a protein in conformational space, the change not only affects thermodynamic properties but also dynamic properties, including the amplitudes of motions on different timescales and rates of conformational transitions. Here we assess the roles of conformational dynamics in allosteric regulation. Two cases are highlighted where NMR spectroscopy and molecular dynamics simulation have been used as complementary approaches to identify residues possibly involved in allosteric communication. Perspectives on contentious issues, e.g., the relation between picosecond-nanosecond local and microsecond-millisecond conformational exchange dynamics, are presented.

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“…and was found to have reduced activity compared to WT Pin1 [30]. W34 appears to be significant for ligand binding the WW domain, and this binding to the WW domain may just simply increase the local concentration of the ligand to the catalytic site, so with perturbed binding, the activity appears to be reduced.…”

Section: Mutations In the Ww Domainmentioning

confidence: 94%

Activity and Affinity of Pin1 Variants

Born

Henen

Vögeli

2019

Preprint

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Pin1 is a peptidyl-prolyl isomerase responsible for isomerizing phosphorylated S/T-P motifs. Pin1 has two domains that each have a distinct ligand binding site, but only its PPIase domain has catalytic activity. Vast evidence supports interdomain allostery of Pin1, with binding of a ligand to its regulatory WW domain impacting activity in the PPIase domain. Many diverse studies have made mutations in Pin1 in order to elucidate interactions that are responsible for ligand binding, isomerase activity, and interdomain allostery. Here, we summarize these mutations and their impact on Pin1's structure and function.

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Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1

Cited by 34 publications

References 59 publications

Neighboring phosphoSer‐Pro motifs in the undefined domain of IRAK1 impart bivalent advantage for Pin1 binding

Neighboring phosphoSer‐Pro motifs in the undefined domain of IRAK1 impart bivalent advantage for Pin1 binding

Protein Allostery and Conformational Dynamics

Activity and Affinity of Pin1 Variants

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