Amide Neighbouring‐Group Effects in Peptides: Phenylalanine as Relay Amino Acid in Long‐Distance Electron Transfer

Nathanael, Joses G.; Gamon, Luke F.; Cordes, Meike; Rablen, Paul R.; Bally, Thomas; Fromm, Katharina M.; Giese, Bernd; Wille, Uta

doi:10.1002/cbic.201800098

Cited by 32 publications

(48 citation statements)

References 42 publications

(28 reference statements)

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“…Electron transfer between an amino acid and a nucleotide might be expected to occur in the direction that yields the lowest-energy exciplex. However, due to the special environment of an RNA-protein binding site (see discussions in refs 57,59 ), this may not necessarily correlate with the redox potentials of isolated nucleotides or aromatic amino acid side chains.…”

Section: Photo-induced Electron Transfer In a π-Stacked Rna-protein Complex May Mediate Radical Reactions Of Cross-linkingmentioning

confidence: 99%

Structural requirements for photo-induced RNA-protein cross-linking

Knörlein

Sarnowski

Vries

et al. 2021

Preprint

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Understanding structure-function relationships of RNA-binding proteins requires knowledge of how they bind RNAs in vivo. RNA-protein interactions are studied using light-induced cross-linking at "zerodistance", yielding nucleotide/amino-acid adducts for mass-spectrometry (MS)-based characterization.However, prerequisites for cross-linking are poorly understood, limiting interpretation of cross-linking data. Here, we report novel insights on cross-linking requirements from studying RBFOX-RRM domain bound to 13 C-labeled variants of its heptaribonucleotide binding element as a model. We probed the influence of nucleotide identity, sequence position and amino-acid composition using tandem-MS to assign cross-links at site-specific resolution. We observed cross-linking at three nucleotides, which were stacked onto phenylalanines. Surprisingly, this stacking was required for neighbouring aminoacids to cross-link, and is apparent in published RNA-protein datasets. We hypothesize that πstacking activates cross-linking via electron transfer, whereafter nucleotide-and peptide radicals, possibly stabilized by capto-dative effects, recombine. These findings should facilitate interpretation of cross-linking data from structural studies and genome-wide datasets. has also been observed with proteins that lack canonical RNA binding domains (RBDs) 1 . Taken together, these features render difficult the prediction of an RBP's substrates based only on a computational search for its consensus RBE. Indeed, recent studies of the RBFOX protein family showed that only one half of the isolated RNA targets contain the RBFOX consensus binding motif and that other motifs presumably bear responsibility for some of its splicing activities [10][11][12] .Many state-of-the-art methods to identify RNA-protein interactions in vivo employ RNA-protein crosslinking induced by UV light [13][14][15][16] . For example, by combining UV cross-linking with mass spectrometry approaches, proteins bound to given RNAs can be identified [17][18][19][20][21][22][23][24] . Conversely, UV cross-linking and immunoprecipitation (CLIP) and related protocols are commonly used to identify RNA-binding sites for given proteins on a transcriptome-wide scale [25][26][27][28][29][30] . Technical advances constantly improve these techniques 18,31,32 , however, a long-standing challenge in structure/mechanism-oriented studies is to identify the points of cross-linking on both the RNA and the protein with site-specific resolution.Recently, we introduced cross-linking of segmentally isotope-labelled RNA and tandem mass spectrometry (CLIR-MS), which identifies the sites of amino acid/ribonucleotide cross-links in a single protocol 32 . In CLIR-MS, RNA regions that are suspected to interact with a protein are synthesized in isotopically labelled light-and heavy variants, so that nucleotides involved in cross-linking events appear as peak doublets in the resulting mass spectrum. By focusing on peak doublets during data analysis, cross-linked amino acids and nucleotides are reliabl...

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Section: Photo-induced Electron Transfer In a π-Stacked Rna-protein Complex May Mediate Radical Reactions Of Cross-linkingmentioning

confidence: 99%

Structural requirements for photo-induced RNA-protein cross-linking

Knörlein

Sarnowski

Vries

et al. 2021

Preprint

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“…S5) further revealed that the aromatic rings of Phe1 and Phe13 in the core of the structure are packed almost as close as is physically possible (distances between ring centers of Phe1 and Phe13 of 4.5 and 5.1 Å), with angled T-shaped geometric orientations, which previous studies have suggested may enable π-π interactions (23). Furthermore, recent experimental evidence has indicated that, even in the absence of π-π stacking, phenylalanines within the hydrophobic core of an amino acid α-helical structure can facilitate long-range electron transport (10, 24). Therefore, our working hypothesis is that the Phe1-Phe13 core is at least one of the features contributing to the e-archaellum conductivity.…”

Section: Observationmentioning

confidence: 99%

The Archaellum of Methanospirillum hungatei Is Electrically Conductive

Walker

Martz

Holmes

et al. 2019

mBio

119

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Microbially produced electrically conductive protein filaments are of interest because they can function as conduits for long-range biological electron transfer. They also show promise as sustainably produced electronic materials. Until now, microbially produced conductive protein filaments have been reported only for bacteria. We report here that the archaellum ofMethanospirillum hungateiis electrically conductive. This is the first demonstration that electrically conductive protein filaments have evolved inArchaea. Furthermore, the structure of theM. hungateiarchaellum was previously determined (N. Poweleit, P. Ge, H. N. Nguyen, R. R. O. Loo, et al., Nat Microbiol 2:16222, 2016,https://doi.org/10.1038/nmicrobiol.2016.222). Thus, the archaellum ofM. hungateiis the first microbially produced electrically conductive protein filament for which a structure is known. We analyzed the previously published structure and identified a core of tightly packed phenylalanines that is one likely route for electron conductance. The availability of theM. hungateiarchaellum structure is expected to substantially advance mechanistic evaluation of long-range electron transport in microbially produced electrically conductive filaments and to aid in the design of “green” electronic materials that can be microbially produced with renewable feedstocks.IMPORTANCEMicrobially produced electrically conductive protein filaments are a revolutionary, sustainably produced, electronic material with broad potential applications. The design of new protein nanowires based on the knownM. hungateiarchaellum structure could be a major advance over the current empirical design of synthetic protein nanowires from electrically conductive bacterial pili. An understanding of the diversity of outer-surface protein structures capable of electron transfer is important for developing models for microbial electrical communication with other cells and minerals in natural anaerobic environments. Extracellular electron exchange is also essential in engineered environments such as bioelectrochemical devices and anaerobic digesters converting wastes to methane. The finding that the archaellum ofM. hungateiis electrically conductive suggests that some archaea might be able to make long-range electrical connections with their external environment.

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“…[69,70] In such cases, aromatic amino acids such as tyrosine, tryptophan, and phenylalanine can serve as sites for electron localization and act as relay stations for electrons moving between donor and acceptor species. [71][72][73][74] Based on this knowledge, an alternative conduction pathway has been proposed in G. sulfurreducens pili, where aromatic amino acids contribute to conduction not via electron delocalization but by acting as charge localization centres themselves. [47,48,75,76] Recently published work reveals more complex interactions could be at play; thin films of G. sulfurreducens protein fibres have been shown to generate current when a water concentration gradient is present in the film.…”

Section: Effect Of Hydration Level On Electron Transfer Ratementioning

confidence: 99%

Challenges in engineering conductive protein fibres: Disentangling the knowledge

2020

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Conductive protein materials are promising candidates for next‐generation bioelectronics due to their genetically‐customizable functionalities, biocompatibility, and bioactivity. We envision that they could be used in a variety of bio‐friendly functional devices, including bio‐electronic interfaces, bio‐energy devices, and sensors. However, their practical uses are limited by gaps in our understanding of charge transport in proteins, and by challenges in establishing reliable data collection methods. Moreover, characterization protocols are not always designed with applications in mind, which hinders engineering developments. Here, we review the effects of sample preparation, environmental conditions (ie, hydration level, pH, temperature), measurement scale (nano, micro, and macro), and geometrical considerations, on the measured electrical properties of proteins. We emphasize the need for standardized methods and collaborations across fields for the design of conductive protein materials, keeping in mind their end goal applications. Our objective for this review is to disentangle the knowledge on protein conductivity, and to clarify the current challenges, limitations, and future possibilities for these biological conductors.

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Amide Neighbouring‐Group Effects in Peptides: Phenylalanine as Relay Amino Acid in Long‐Distance Electron Transfer

Cited by 32 publications

References 42 publications

Structural requirements for photo-induced RNA-protein cross-linking

Structural requirements for photo-induced RNA-protein cross-linking

The Archaellum of Methanospirillum hungatei Is Electrically Conductive

Challenges in engineering conductive protein fibres: Disentangling the knowledge

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