Molecular Mechanism of Pin1–Tau Recognition and Catalysis

Eichner, Timo; Kutter, Steffen; Labeikovsky, Wladimir; Buosi, Vanessa

doi:10.1016/j.jmb.2016.03.009

Cited by 23 publications

(52 citation statements)

References 94 publications

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“…Compared with 38 ms of the 1 H T 2 relaxation time of the 68-residue peptide [40], the p231-6H3G peptide consisting of 25 amino acids showed the longer T 2 (about 70 ms) (Fig. Similar observations were reported by Smet et al [18] and Eichner et al [19], in which the PPIase domain of Pin1 interacted with the pThr231-Pro232 bond very weakly but did not catalyze its isomerization, while its WW domain bound to the bond with moderate affinity. Considering the number and composition of amino acid residues, the difference in T 2 of both peptides strongly suggests the p231-6H3G peptide is monomeric, because T 2 negatively depends on the rotational correlation time of molecule given by the Stokes-Einstein equation.…”

Section: Resultssupporting

confidence: 81%

“…This hypothesis is supported by some experimental results in which NFT was colocalized with Pin1 [13,14] and NFT was more accumulated in transgenic mouse without a peptidyl-prolyl isomerase (PPIase) Pin1 [15]. Nuclear magnetic resonance (NMR) studies showed that the peptides had extremely low cis-isomeric ratios [11,18] and Pin1 did not isomerize the pThr231-Pro232 bond [19]; thus, contradicting 'cistauosis'. the phosphorylated serine or threonine preceding a proline (pSer/pThr-Pro) motif, and it is expected to convert the cis isomer of Tau to the trans one; thus, preventing the accumulation of NFT [16].…”

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confidence: 82%

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The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

et al. 2018

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In Alzheimer's, the disease-related protein Tau is hyperphosphorylated and aggregates into neurofibrillary tangles (NFT). The cis isomer of the phosphorylated Thr231-Pro232 has been proposed as a precursor of aggregation ('Cistauosis'), but this aggregation scheme is not yet completely accepted. Here, we synthesized peptides comprising a phosphorylated region including Thr231-Pro232 and an aggregation-core region R1 to investigate isomer-specific-aggregation of Tau. The phosphorylated peptide formed amyloid-like aggregation. This aggregation was observed even in the presence of the catalytic domain of the peptidyl-prolyl-isomerase Pin1, which preferentially converts the cis isomer to the trans isomer, but decreased drastically in the presence of the WW domain of Pin1 selectively binding to the trans isomer. These results indicate that the trans isomer is aggregation-prone and that the WW domain of Pin1 effectively inhibits its aggregation.

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 82%

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

et al. 2018

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“…96 However, what determines a Pin1 “client” has been called into question. 97 Indeed, putative Pin1 binding sites have been challenging to substantiate, such as the unconventional bivalent interaction as seen with protein kinase C 98 or the role in controlling phosphorylated tau function for microtubule assembly and stabilization. 99 …”

Section: Roles Of Ppiases In Diseasementioning

confidence: 99%

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

2016

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Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These “clients” include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the “undruggable” features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.

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“…Pin1 consists of two functional domains, the WW- at the N-terminus and the PPIase-domains at the C-terminus, covalently fastened by a flexible linker (amino acids 38–53) of 15-residues [9,18]. The linker allows the domains to rotate independently of each other [19,20]. The PPIase domain catalyzes specifically the cis / trans isomerization of pSer/pThr-peptidyl-prolyl bonds.…”

Section: Pin1 Characterization: Structure Regulation and Subcellumentioning

confidence: 99%

“…The WW domain (type IV) binds, but does not catalyze, similar epitopes [20,21]. Upon Pin1 binding of the specific substrate to the previous phosphorylated S/T-P motifs by proline directed kinases, the two functional domains of Pin1 interact partially with each other in a substrate-dependent manner [20,22,23]. Recognition of the substrate determines a loss of flexibility of residue side-chains in the region between the catalytic loop and the inter-domain surface.…”

Section: Pin1 Characterization: Structure Regulation and Subcellumentioning

confidence: 99%

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

Bianchi

Manco

2018

IJMS

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Prolyl isomerases (Peptidylprolyl isomerase, PPIases) are enzymes that catalyze the isomerization between the cis/trans Pro conformations. Three subclasses belong to the class: FKBP (FK506 binding protein family), Cyclophilin and Parvulin family (Pin1 and Par14). Among Prolyl isomerases, Pin1 presents as distinctive feature, the ability of binding to the motif pSer/pThr-Pro that is phosphorylated by kinases. Modulation of Pin1 is implicated in cellular processes such as mitosis, differentiation and metabolism: The enzyme is dysregulated in many diverse pathological conditions, i.e., cancer progression, neurodegenerative (i.e., Alzheimer’s diseases, AD) and metabolic disorders (i.e., type 2 diabetes, T2D). Indeed, Pin1 KO mice develop a complex phenotype of premature aging, cognitive impairment in elderly mice and neuronal degeneration resembling that of the AD in humans. In addition, since the molecule modulates glucose homeostasis in the brain and peripherally, Pin1 KO mice are resistant to diet-induced obesity, insulin resistance, peripheral glucose intolerance and diabetic vascular dysfunction. In this review, we revise first critically the role of Pin1 in neuronal development and differentiation and then focus on the in vivo studies that demonstrate its pivotal role in neurodegenerative processes and glucose homeostasis. We discuss evidence that enables us to speculate about the role of Pin1 as molecular link in the pathogenesis of type 3 diabetes i.e., the clinical association of dementia/AD and T2D.

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Molecular Mechanism of Pin1–Tau Recognition and Catalysis

Cited by 23 publications

References 94 publications

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

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