Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

Zheng, Jing; Liu, Cong; Sawaya, M.R.; Balraju, V.; Khan, Shafiullah; Woods, R. Jeremy; Eisenberg, David; Goux, Warren J.; Nowick, James S.

doi:10.1021/ja110545h

Cited by 117 publications

(149 citation statements)

References 73 publications

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“…To verify this conclusion, we performed two control experiments. First we confirmed that the altered kinetics are due to disruption of the intermediate rather than the fibril β-sheets by adding Mac [31][32][33][34][35][36][37] . It seeds I26P fibril formation as it does with wild-type hIAPP, thus proving I26P can readily form fibrils and the proline mutation is not simply incompatible with the fibril structure.…”

Section: Resultssupporting

confidence: 55%

“…Thus, the heptapeptide strand of the macrocycle is designed to bind to amyloid β-sheets with a matching sequence, whereas the other strand prevents further elongation. Similar macrocycles have been used previously to study the aggregation of a τ-derived hexapeptide, amyloid-β, β2-microglobulin, and truncated α-synuclein (33,34).…”

Section: Resultsmentioning

confidence: 99%

“…2B). Two macrocycles have sequences that overlap the N-terminal β-sheet of the fibrils (Mac [11][12][13][14][15][16][17] and Mac [15][16][17][18][19][20][21] ), two overlap the C-terminal sheet (Mac [26][27][28][29][30][31][32] and Mac [31][32][33][34][35][36][37], and one targets the FGAIL region under investigation (Mac [21][22][23][24][25][26][27] ). The sequences of the macrocycles are given in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3. Conformational free energy map for the dimerization of hIAPP in terms of order parameters Q [8][9][10][11][12][13][14][15][16] and Q [27][28][29][30][31][32][33][34][35] . Contour lines are drawn every 2.5 kJ/mol.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Buchanan

Dunkelberger

Tran

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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245

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Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.inhibitors | aggregation pathway | vibrational coupling T he misfolding of proteins into β-sheet-rich amyloid fibrils is associated with the pathology of more than 20 human diseases, including Alzheimer's, Parkinson, and Huntington diseases (1). Amyloid plaques are formed by masses of fibrils, but growing evidence suggests that the toxic species may be prefibrillar intermediates (2, 3). As a result, there is much interest in understanding the mechanism by which these proteins form fibrils and identifying intermediates in the aggregation pathway. However, obtaining structural information about intermediate species is difficult due to their transient nature. Solid-state NMR (ssNMR) and X-ray crystallography provide high-resolution structures of fibrils (4, 5) and optical techniques can track structural changes in real time (6, 7), but few techniques have both the structural and the temporal resolution to extract specific structural details about intermediates. Fragments have been trapped in intriguing oligomeric structures that may represent intermediate states (5,8) and transient secondary structures are known to exist from circular dichroism measurements and other experiments (9-11), but for full-length proteins it has been difficult to identify the specific residues that contribute to the secondary structure and thus understand their role in the aggregation mechanism. In this paper, we use 2D infrared (2D IR) spectroscopy and isotope labeling to monitor the structural evolution of the full-length human islet amyloid polypeptide (hIAPP or amylin), a 37-residue peptide implicated in type 2 diabetes. We observe the formation of a structured prefibrillar intermediate in a region that has long been known to influence aggregation, but that does not form well-ordered cross-β structure in the amyloid fibril. Its presence provides unique structural insights into the mechanism of amyloid aggregation and helps unify many seemingly inconsistent prior studies.Many studies on hIAPP have focused ...

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Buchanan

Dunkelberger

Tran

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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245

345

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“…The VQIVYK peptide, termed PHF6, is a highly aggregative short segment located in the third repeat of the MT-binding region of the tau protein [17,18], which can assume the β-sheet structures necessary for the aggregation of tau into oligomers and NFTs [17,19]. This peptide is widely used as a model for studying tau aggregation and examining candidate inhibitors [20,21,22,23,24,25,26]. …”

Section: Introductionmentioning

confidence: 99%

Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity

Frenkel-Pinter

Sharon²,

Scherzer-Attali³

et al. 2016

Neurodegener Dis

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Alzheimer's disease (AD) is the most abundant tauopathy and is characterized by Aβ-derived plaques and tau-derived tangles, resulting from the unfolding of the corresponding monomeric subunits into ordered β-sheet oligomers and fibrils. Intervening in the toxic aggregation process is a promising therapeutic approach, but, to date, a disease-modifying therapy is neither available for AD nor for other tauopathies. Along these lines, we have previously demonstrated that a small naphthoquinone-tryptophan hybrid, termed NQTrp, is an effective modulator of tauopathy in vitro and in vivo. However, NQTrp is difficult to synthesize and is not very stable. Therefore, we tested whether a more stable and easier-to-synthesize modified version of NQTrp, containing a Cl ion, namely Cl-NQTrp, is also an effective inhibitor of tau aggregation in vitro and in vivo. Cl-NQTrp was previously shown to efficiently inhibit the aggregation of various amyloidogenic proteins and peptides. We demonstrate that Cl-NQTrp inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau, and alleviates tauopathy symptoms in a transgenic Drosophila model through the inhibition of tau aggregation-engendered toxicity. These results suggest that Cl-NQTrp could be a unique potential therapeutic for AD since it targets aggregation of both Aβ and tau.

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Crystal structure of the human tau PHF core domain VQIINK complexed with the Fab domain of monoclonal antibody Tau2r3

et al. 2020

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Neurofibrillary tangles formed by abnormally aggregated tau protein are a histopathological feature of tauopathies. A tau aggregation inhibitor is a potential therapeutic agent for tauopathies. In this study, we prepared a monoclonal antibody for tau, monoclonal antibody to tau protein (Tau2r3), using as epitope the 272 GGKVQIINKKLD 283 peptide in the microtubule-binding domain of tau, the key region mediating tau aggregation. We show that Tau2r3 clearly inhibits tau aggregation. To analyze the inhibition mechanism of Tau2r3, we solved the crystal structure of the Fab domain of Tau2r3 (Fab2r3) in complex with the VQIINK peptide. In the Fab2r3-VQIINK structure, the second and sixth polar residues and the fourth hydrophobic residue of VQIINK are crucial for binding to Fab2r3. The structural data for the Fab2r3-VQIINK complex could contribute to the design of new tau aggregation inhibitors.

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Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

Cited by 117 publications

References 73 publications

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity

Crystal structure of the human tau PHF core domain VQIINK complexed with the Fab domain of monoclonal antibody Tau2r3

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