Identification and Structural Characterization of the N-terminal Amyloid Core of Orb2 isoform A

Cervantes, Silvia A.; Bajakian, Thalia; Soria, Maria A.; Falk, Alexander S.; Service, Rachel J.; Langen, Ralf; Siemer, Ansgar B.

doi:10.1038/srep38265

Cited by 33 publications

(77 citation statements)

References 49 publications

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“…This kind of architecture may be a more general feature of functional amyloids, as HET-s is itself also considered a functional amyloid. Various functional amyloids have been identified or proposed in higher organisms, some of which have been probed by ssNMR: the Pmel17 protein involved in the melanin deposition [108], memory-related CPEB and Orb2 proteins [109–111], RIP1/RIP3 kinases involved in necrosis [112], and reversible fibrils formed by β-endorphin [113]. …”

Section: Functional Amyloidsmentioning

confidence: 99%

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Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

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The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation. A central focus is on disease-related amyloid fibrils and oligomers involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. SSNMR-enabled structural and dynamics-based findings are surveyed, along with a number of resulting emerging themes that appear common to different amyloidogenic proteins, such as their compact alternating short-β-strand/β-arc amyloid core architecture. Concepts, methods, future prospects and challenges are discussed.

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Section: Functional Amyloidsmentioning

confidence: 99%

“…These studies reveal another common feature of amyloidogenic proteins: that only relatively small portions of the protein end up in the β-sheet-based amyloid core [75, 91, 92, 111]. The non-amyloid portions can contain folded domains, isolated secondary structure elements, or be dynamically disordered (Fig.…”

Section: Recurring Themesmentioning

confidence: 99%

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

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“…In the past decade, solid-state NMR has been used to study a variety of biological systems such as HIV-1 capsid protein assemblies [6][7][8][9][10][11], 300 kDa GB1-antibody complexes [12,13], and membrane-bound influenza M2 proton channels [14][15][16]. Such NMR studies have also provided measurements of protein dynamics [17][18][19] and identification of disordered regions [20][21][22][23][24].Research in recent years on intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) has highlighted the importance of disordered regions in the function of many proteins. These regions can be essential for correct function, by mediating protein-protein interactions, protein-DNA interactions, and protein-RNA interactions [25].…”

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confidence: 99%

Strategies for identifying dynamic regions in protein complexes: flexibility changes accompany methylation in chemotaxis receptor signaling states

Malik

Wahlbeck

Thompson

2020

Preprint

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AbstractBacterial chemoreceptors are organized in arrays composed of helical receptors arranged as trimers of dimers, coupled to a histidine kinase CheA and a coupling protein CheW. Ligand binding to the external domain inhibits the kinase activity, leading to a change in the swimming behavior. Adaptation to an ongoing stimulus involves reversible methylation and demethylation of specific glutamate residues. However, the exact mechanism of signal propagation through the helical receptor to the histidine kinase remains elusive. Dynamics of the receptor cytoplasmic domain is thought to play an important role in the signal transduction, and current models propose inverse dynamic changes in different regions of the receptor. We hypothesize that the adaptational modification (methylation) controls the dynamics by stabilizing a partially ordered domain, which in turn modulates the binding of the kinase, CheA. We investigated the difference in dynamics between the methylated and unmethylated states of the chemoreceptor using solid-state NMR. The unmethylated receptor (CF4E) shows increased flexibility relative to the methylation mimic (CF4Q). Methylation helix 1 (MH1) has been shown to be flexible in the methylated receptor. Our analysis indicates that in addition to MH1, methylation helix 2 also becomes flexible in the unmethylated receptor. In addition, we have demonstrated that both states of the receptor have a rigid region and segments with intermediate dynamics. The strategies used in the study for identifying dynamic regions are applicable to a broad class of proteins and protein complexes with intrinsic disorder and dynamics spanning multiple timescales.Graphical AbstractHighlightsReceptors exhibit greater ns timescale dynamics in unmethylated vs methylated stateMethylation helix 2 likely involved in increased flexibility of unmethylated stateDynamics occur on multiple timescales in both states of the receptor

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“…Moreover, the conformational trends within the PLD that precedes amyloid formation appears to be different among species. Thus, while the ApCPEB PLD forms α-helical coiled-coils in vitro and assembles into multimers to enhance amyloid aggregation [14][15][16] , the recombinant Orb2 PLD remains as a random coil conformation, which is able to oligomerize and form amyloid structures whose β-sheet core seems not to include the Q-rich domain 17 . By contrast, recent cryo-EM data revealed that Drosophila Orb2 from adult heads forms a threefold-symmetric hydrophilic amyloid core based on the Q-rich stretch 18 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

Mingo

López-García

Hervás

et al. 2020

Preprint

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The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), is an RNA-binding protein which in its soluble state is localized in membraneless neuronal RNA granules keeping target mRNAs in a repressed state. The stimulus-dependent aggregation of CPEB3 activates target mRNAs translation, a central event for the maintenance of long-term memory-related synaptic plasticity in mammals. To date, the molecular determinants that govern both connected events remain unclear. Here, to gain insight into these processes, the biophysical properties of the human CPEB3 (hCPEB3) are characterized. We found that hCPEB3 homotypic condensation is mainly driven by hydrophobic interactions and occurs under physiological conditions. Moreover, hCPEB3 biomolecular condensates are dynamic inside living cells, whose localization and stabilization are mediated by its RNA-recognition domains.In contrast, the hCPEB3 polar N-terminal region is crucial for hCPEB3 amyloid-like aggregation in vitro, which is disrupted by the polyglutamine binding peptide 1 (QBP1), Aβ42 seeds and Hsp70, highlighting the importance of the Q4RQ4 tract as well as the hydrophobic residues for hCPEB3 functional aggregation. Based on these findings, we postulate a model for hCPEB3's role in memory persistence that advances a rather sophisticated control for hCPEB3 condensate dissociation and amyloid-like formation to achieve its physiological function.hCPEB3's demixing and amyloidogenesis Highlights • hCPEB3 forms toxic intermediates that persist longer than in other functional amyloids.• RNA-recognition domains stabilize hCPEB3 granule formation and dynamics.• Different segments within hCPEB3 promote amyloidogenesis and liquid demixing.• hCPEB3 amyloid formation requires both hydrophobic and polyQ segments. Graphical AbstracthCPEB3's demixing and amyloidogenesis

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Identification and Structural Characterization of the N-terminal Amyloid Core of Orb2 isoform A

Cited by 33 publications

References 49 publications

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Strategies for identifying dynamic regions in protein complexes: flexibility changes accompany methylation in chemotaxis receptor signaling states

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

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