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

Ikura, Teikichi; Tochio, N.; Kawasaki, Ryo; Matsuzaki, Mizuki; Narita, Akihiro; Kikumoto, Mahito; Utsunomiya‐Tate, Naoko; Tate, Shin‐ichi; Ito, Nobuyasu

doi:10.1002/1873-3468.13218

Cited by 7 publications

(6 citation statements)

References 42 publications

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“…One study suggested that the trans isomer of tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation. 530 It could be possible that both trans-tau and cis-tau are able to aggregate, depends in the environment in the experimental conditions to change their energy landscape. Accelerated MD were used to explore the conformational landscape of the tau segment containing the phosphorylated-Thr( 231)-Pro(232) motif.…”

Section: Impact Of Phosphorylation and Other Ptm On Tau Aggregationmentioning

confidence: 99%

“…Other conflicting results were also observed in the proneness of aggregation. One study suggested that the trans isomer of tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation . It could be possible that both trans-tau and cis-tau are able to aggregate, depends in the environment in the experimental conditions to change their energy landscape.…”

Section: Extensive Simulations On Monomers and Small Oligomersmentioning

confidence: 99%

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

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Section: Impact Of Phosphorylation and Other Ptm On Tau Aggregationmentioning

confidence: 99%

Section: Extensive Simulations On Monomers and Small Oligomersmentioning

confidence: 99%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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“…It is possible that other factors or modifications promote tau aggregation. The ratio of cis/trans isoforms may affect fibrillarization and in vitro data suggest that in particular the trans isomer of a tau peptide is prone to aggregate (125). Isomerization is regulated by the protein Pin1, which binds to the PRR of tau.…”

Section: Pathological Changes Of the Interactions Of The Microtubule Binding Regionmentioning

confidence: 99%

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

2020

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Tau protein (MAPT) is classified as a microtubule-associated protein (MAP) and is believed to regulate the axonal microtubule arrangement. It belongs to the tau/MAP2/MAP4 family of MAPs that have a similar microtubule binding region at their carboxy-terminal half. In tauopathies, such as Alzheimer's disease, tau is distributed more in the somatodendritic compartment, where it aggregates into filamentous structures, the formation of which correlates with cognitive impairments in patients. While microtubules are the dominant interaction partners of tau under physiological conditions, tau has many additional interaction partners that can contribute to its physiological and pathological role. In particular, the amino-terminal non-microtubule binding domain (N-terminal projection region, NTR) of tau interacts with many partners that are involved in membrane organization. The NTR contains intrinsically disordered regions (IDRs) that show a strong evolutionary increase in the disorder and may have been the basis for the development of new, tau-specific interactions. In this review we discuss the functional organization of the tau protein and the special features of the tau non-microtubule binding region also in the connection with the results of Tau KO models. We consider possible physiological and pathological functions of tau's non-microtubule interactions, which could indicate that interactions mediated by tau's NTR and regulated by far-reaching functional interactions of the PRR and the extreme C-terminus of tau contribute to the pathological processes.

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“…The structure of full-length Pin1 was determined by X-ray crystallography, after introducing five mutations G44E/ G45N/K46L/N47Y/G48F in the linker region between the two domains, and expressing and purifying this protein [12]. The full-length C113A mutant was obtained by substituting a hydrogen for the sulfur Sγ of C113.…”

Section: Simulationsmentioning

confidence: 99%

“…1). In additional experiments, the functions of this mutant were shown to be equivalent to those of wild-type Pin1 [12]. Therefore, we dealt with this mutant protein as the wild-type protein in this study, and then obtained the C113A mutant by substituting a hydrogen for the sulfur Sγ of C113.…”

Section: Initial Structuresmentioning

confidence: 99%

Mutational effects of Cys113 on structural dynamics of Pin1

2019

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Pin1 is a peptidyl-prolyl isomerase (PPIase) which catalyzes cis/trans isomerization of pS/pT-P bond. Its activity is related to various cellular functions including suppression of Alzheimer's disease. A cysteine residue C113 is known to be important for its PPIase activity; a mutation C113A reduced the activity by 130-fold. According to various nuclear magnetic resonance experiments for mutants of C113 and molecular dynamics (MD) simulation of wild-type Pin1, the protonation sate of Sγ of C113 regulates the hydrogen-bonding network of the dualhistidine motif (H59, H157) whose dynamics may affect substrate binding ability. However, it was still unclear why such local dynamic changes altered the PPIase activity of Pin1. In this study, we performed 500 ns of MD simulations of full-length wild-type Pin1 and C113A mutant in order to elucidate why the mutation C113A drastically reduced the PPIase activity of Pin1. The principal component analysis for both MD trajectories clearly elucidated that the mutation C113A suppressed the dynamics of Pin1 because it stabilized a hydrogenbond between Nε of H59 and Oγ of S115. In the dynam-ics of wild-type protein, the phosphate binding loop (K63-S71) as well as the interdomain hinge showed the closed-open dynamics which correlated with the change of the hydrogen-bonding network of the dual-histidine motif. In contrast, in the dynamics of C113A mutant, the phosphate binding loop took only the closed conformation together with the interdomain hinge. Such closedopen dynamics must be essential for the PPIase activity of Pin1.Peptidyl-prolyl isomerase (PPIase) catalyzes cis/trans isomerization of a peptide bond preceding a proline residue. Peptidyl-prolyl isomerase NIMA-interacting 1 (Pin1) is a member of the parvulin family of PPIases which specifically catalyze a sequence motif including a phosphoserine or a phosphothreonine followed by a proline (pS/pT-P) [1,2]. Pin1 functions as a molecular switch in various cellular processes including regulation of mitosis [1,3], cell growth [4], maintenance of germinal centers [5], and as a suppressor of neurofibrillary tangles in Alzheimer's disease [6]. Pin1 consists of two domains, the N-terminal WW domain and the Five-hundred ns of MD simulations of full-length wild-type Pin1 and C113A mutant were performed in order to elucidate why a mutation C113A drastically reduced the PPIase activity of Pin1. In the dynamics of wild-type protein, the phosphate binding loop (K63-S71) as well as the interdomain hinge showed the closed-open dynamics which correlated with the change of the hydrogen-bonding network of the dual-histidine motif. In contrast, in the dynamics of C113A mutant, the phosphate binding loop took only the closed conformation together with the interdomain hinge. Such closed-open dynamics must be essential for the PPIase activity of Pin1.

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

Cited by 7 publications

References 42 publications

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

Mutational effects of Cys113 on structural dynamics of Pin1

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