Peptides

  • Article
    | Open Access

    Borosins are ribosomally encoded and posttranslationally modified peptide (RiPP) natural products featuring amide-backbone α-N-methylation. Here, the authors report the discovery and characterization of type IV borosin ‘split’ pathways encoding distinct, separate α-N-methyltransferases and precursor peptide substrates.

    • Fredarla S. Miller
    • , Kathryn K. Crone
    •  & Michael F. Freeman
  • Article
    | Open Access

    C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/proteins of great therapeutic potential, but their chemical synthesis is challenging. Here, the authors report a protocol for the synthesis of vinyl C-glycosyl amino acids and peptides, via a Ni-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with glycosyl bromides.

    • Yan-Hua Liu
    • , Yu-Nong Xia
    •  & Biao Yu
  • Article
    | Open Access

    Self-assembling peptides have a range of potential applications but developing self-assembling sequences can be challenging. Here, the authors report on a one-bead one-compound combinatorial library where fluorescence is used to detect the potential for self-assembly and identified candidates are evaluated.

    • Pei-Pei Yang
    • , Yi-Jing Li
    •  & Kit S. Lam
  • Article
    | Open Access

    α-Synuclein (αS) aggregation is a driver of several neurodegenerative disorders. Here, the authors identify a class of peptides that bind toxic αS oligomers and amyloid fibrils but not monomeric functional protein, and prevent further αS aggregation and associated cell damage.

    • Jaime Santos
    • , Pablo Gracia
    •  & Salvador Ventura
  • Article
    | Open Access

    Self-assembling peptides (SAPs) can be used to build biomaterials, but genetically encoded SAPs have rarely been used as building blocks in cells. Here, the authors design a SAP that can be genetically fused to target proteins to induce their intracellular clustering and modulate their signaling functions.

    • Takayuki Miki
    • , Taichi Nakai
    •  & Hisakazu Mihara
  • Article
    | Open Access

    Cyclic peptides are of particular interest due to their pharmacological properties, but their design for binding to a target protein is challenging. Here, the authors present a computational “anchor extension” methodology for de novo design of cyclic peptides that bind to the target protein with high affinity, and validate the approach by developing cyclic peptides that inhibit histone deacetylases 2 and 6.

    • Parisa Hosseinzadeh
    • , Paris R. Watson
    •  & David Baker
  • Article
    | Open Access

    MALDI-mass spectrometry imaging (MSI) can reveal the distribution of proteins in tissues but tools for protein identification and annotation are sparse. Here, the authors develop an open-source bioinformatic workflow for false discovery rate-controlled protein annotation and spatial mapping from MALDI-MSI data.

    • G. Guo
    • , M. Papanicolaou
    •  & A. C. Grey
  • Article
    | Open Access

    Developing molecules that emulate the properties of naturally occurring ice-binding proteins (IBPs) is a daunting challenge. Here, the authors demonstrate the use of phage display for the identification of short peptide mimics of IBPs, which resulted in the identification of a cyclic ice-binding peptide containing just 14 amino acids.

    • Corey A. Stevens
    • , Fabienne Bachtiger
    •  & Harm-Anton Klok
  • Article
    | Open Access

    Methods for selective modification of the N-terminus of proteins are of high interest, but mostly require specific amino acid residues. Here, the authors report a selective and fast method for N-terminal modification of proteins based on quinone-mediated oxidation of the alpha-amine to aldehyde or ketone, and apply it to diverse proteins.

    • Siyao Wang
    • , Qingqing Zhou
    •  & Ping Wang
  • Article
    | Open Access

    14-3-3 proteins recognize phosphorylated motifs within numerous protein partners. Here, the authors characterize the binding of all human 14-3-3 isoforms to four E6 oncoproteins, and identify a fixed order of 14-3-3 binding affinities that is conserved in 14-3-3:phosphoprotein interactions across the proteome.

    • Gergo Gogl
    • , Kristina V. Tugaeva
    •  & Nikolai N. Sluchanko
  • Article
    | Open Access

    RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.

    • Emiko Mihara
    • , Satoshi Watanabe
    •  & Junichi Takagi
  • Article
    | Open Access

    Many alternative ORFs are co-encoded with characterized proteins, but their function is often not understood. Here, the authors discover that ribosomal protein L36 is co-encoded with alternative protein, which they identify as an upstream regulator of PI3K-AKT-mTOR signaling.

    • Xiongwen Cao
    • , Alexandra Khitun
    •  & Sarah A. Slavoff
  • Article
    | Open Access

    Apelin and AVP have opposing effects water balance in humans and rodents. Here, the authors report that a metabolically stable apelin-17 analog, by acting at the kidney level, reduces AVP-induced antidiuresis and improves hyponatremia in rodents, demonstrating a potential approach for treating water metabolism disorders.

    • Adrien Flahault
    • , Pierre-Emmanuel Girault-Sotias
    •  & Catherine Llorens-Cortes
  • Article
    | Open Access

    FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties.

    • Cornelia Hermes
    • , René Richarz
    •  & Max Crüsemann
  • Article
    | Open Access

    Current histone microarrays cannot be used to directly study the transient interactions of histone deacetylases (HDACs). Here, the authors show that hydroxamic acid-modified microarrays can capture HDACs, provide insights into their substrate specificity, and serve to develop peptide inhibitors.

    • Carlos Moreno-Yruela
    • , Michael Bæk
    •  & Christian A. Olsen
  • Article
    | Open Access

    The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.

    • Christos Kontos
    • , Omar El Bounkari
    •  & Jürgen Bernhagen
  • Article
    | Open Access

    ADP-ribosylated peptides are important molecular tools, however, the lack of effective synthetic methods hinders the access to their complex structures. Here, the authors present a biomimetic α-selective ribosylation reaction coupled with click chemistry ultimately providing a two-step modular synthesis of α-ADP-ribosylated peptides.

    • Anlian Zhu
    • , Xin Li
    •  & Lingjun Li
  • Article
    | Open Access

    Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.

    • Hélène Adihou
    • , Ranganath Gopalakrishnan
    •  & Herbert Waldmann
  • Article
    | Open Access

    Oxepinamides are a class of fungal oxepins with biological activities. Here, the authors elucidate the biosynthetic pathway of oxepinamide F from Aspergillus ustus and show that it involves enyme-catalysed oxepin ring formation, hydroxylation-induced double bond migration, epimerization and methylation.

    • Liujuan Zheng
    • , Haowen Wang
    •  & Shu-Ming Li
  • Article
    | Open Access

    Backbone extended monomers are poorly compatible with the natural ribosomes, impeding their polymerization into polypeptides. Here the authors design non-canonical amino acid analogs with cyclic structures or extended carbon chains and used an engineered ribosome to improve tRNA-charging and incorporation into peptides.

    • Joongoo Lee
    • , Kevin J. Schwarz
    •  & Michael C. Jewett
  • Article
    | Open Access

    Mass spectrometry-based proteomics is the method of choice for the global mapping of post-translational modifications, but matching and scoring peaks with unknown masses remains challenging. Here, the authors present a refined open search strategy to score all peaks with higher sensitivity and accuracy.

    • Fengchao Yu
    • , Guo Ci Teo
    •  & Alexey I. Nesvizhskii
  • Article
    | Open Access

    Mitochondrial apoptosis is controlled by BCL2 family proteins, and the BH3-only proteins often act as sensors that transmit apoptotic signals. Here the authors show how the BH3-only proteins BMF and HRK can directly activate the BCL2 protein BAK and interact with BAK through an alternative binding groove.

    • Kaiqin Ye
    • , Wei X. Meng
    •  & Haiming Dai
  • Article
    | Open Access

    Synthetic peptide libraries can access broad chemical space, but generally examine only ~ 106 compounds. Here, the authors show that in-solution affinity selection, interfaced with nLC-MS/MS sequencing, can identify binders from fully randomized synthetic libraries of 108 members.

    • Anthony J. Quartararo
    • , Zachary P. Gates
    •  & Bradley L. Pentelute
  • Article
    | Open Access

    Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.

    • Shuaijiang Jin
    • , Roberto J. Brea
    •  & Neal K. Devaraj
  • Article
    | Open Access

    Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.

    • Lauren E. Stopfer
    • , Joshua M. Mesfin
    •  & Forest M. White
  • Article
    | Open Access

    Trefoil factors (TFFs) protect the mucosa and have various reported binding activities, but whether they share a common interaction mechanism has remained unclear. Here, the authors provide structural and biochemical evidence that all three human TFFs are divalent lectins that recognise the same disaccharide.

    • Michael A. Järvå
    • , James P. Lingford
    •  & Ethan D. Goddard-Borger
  • Article
    | Open Access

    Antibodies conjugated to bioactive compounds can allow targeted delivery of therapeutics. Here the authors present a strategy for fusing nanobodies to suboptimal GPCR peptide ligands to potently and selectively activate receptors.

    • Ross W. Cheloha
    • , Fabian A. Fischer
    •  & Hidde L. Ploegh
  • Article
    | Open Access

    NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death.

    • Jouliana Sadek
    • , Michael G. Wuo
    •  & Paramjit S. Arora
  • Article
    | Open Access

    Asparaginyl endopeptidases (AEPs) catalyze the cyclization step during the biosynthesis of cyclic peptides in plants. Here, the authors report a recombinantly produced AEP that catalyzes the backbone cyclization of a linear cyclotide precursor and an engineered analog with high efficiency and in a pH-dependent manner.

    • Junqiao Du
    • , Kuok Yap
    •  & David J. Craik
  • Article
    | Open Access

    Most epigenetic regulator inhibitors target tunnels of active sites, rather than the peptide binding groove, leading to concerns with low selectivity. Here the authors use an amber obligate phage library to rapidly identify isoform-selective inhibitors of SIRT2.

    • Jeffery M. Tharp
    • , J. Trae Hampton
    •  & Wenshe Ray Liu
  • Article
    | Open Access

    Non-canonical HLA-bound peptides from presumed non-coding regions are potential targets for cancer immunotherapy, but their discovery remains challenging. Here, the authors integrate exome sequencing, transcriptomics, ribosome profiling, and immunopeptidomics to identify tumor-specific non-canonical HLA-bound peptides.

    • Chloe Chong
    • , Markus Müller
    •  & Michal Bassani-Sternberg
  • Article
    | Open Access

    Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.

    • Bonny Gaby Lui
    • , Nadja Salomon
    •  & Ugur Sahin
  • Article
    | Open Access

    Acetylation of p53 is critical for its transcriptional activity and its tumour suppressive function. Here, the authors show that PBRM1 is a reader protein for p53′s C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.

    • Weijia Cai
    • , Liya Su
    •  & Haifeng Yang
  • Article
    | Open Access

    Chiral inversion of amino acids is thought to modulate the structure and function of amyloid beta (Aβ) but these processes are poorly understood. Here, the authors develop an ion mobility-mass spectrometry based approach to study chirality-regulated structural features of Aβ fragments and their influence on receptor recognition.

    • Gongyu Li
    • , Kellen DeLaney
    •  & Lingjun Li
  • Article
    | Open Access

    The activation of drugs within cellular systems may provide targeted therapies for cancer. Here, the authors make a drug delivery system that is activated within the cell and exploits XIAP expression to cleave a linker region, resulting in the self-assembly of the system and drug release within cancer cells.

    • Hong-Wei An
    • , Li-Li Li
    •  & Yuliang Zhao
  • Article
    | Open Access

    Peptide self-assembly into fibres is prevalent in nature in normal tissue and in degenerative diseases. Here, the authors report on the coupling of liquid cell TEM with MALDI-imaging mass spectrometry to study processes of peptide fibre formation, in solution, in real time with nanoscale resolution.

    • Mollie A. Touve
    • , Andrea S. Carlini
    •  & Nathan C. Gianneschi
  • Article
    | Open Access

    Wet–dry cycling is regarded as a possible driving force of condensation reactions under prebiotic conditions. Here, the authors propose that water uptake by deliquescent minerals could have facilitated the wet phase and simulate this scenario using the oligomerization of glycine as a model reaction.

    • Thomas D. Campbell
    • , Rio Febrian
    •  & Paul J. Bracher
  • Article
    | Open Access

    Developing inhibitors that target specific protein-protein interactions (PPIs) is challenging. Here, the authors show that target selectivity and PPI blocking can be achieved simultaneously with PPI inhibitors that contain two functional modules, and create a paralog-selective PSD-95 inhibitor as proof-of-concept.

    • Charlotte Rimbault
    • , Kashyap Maruthi
    •  & Matthieu Sainlos
  • Article
    | Open Access

    Existing methods for protein polymer engineering suffer from low efficiency especially for synthesis large size polyproteins. Here, Deng et al. construct homo-polymer and co-polymer up to decamer by stepwise ligation and cleavage validated by atomic force microscopy-based single-molecule force spectroscopy.

    • Yibing Deng
    • , Tao Wu
    •  & Peng Zheng
  • Article
    | Open Access

    The suppressor of cytokine signaling 2 (SOCS2) is a component of the Cullin5 E3 ubiquitin ligase complex. Here the authors provide insights into substrate recognition and specificity of SOCS2 by determining the crystal structures of the SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from two of its substrates the growth hormone receptor and erythropoietin receptor.

    • Wei-Wei Kung
    • , Sarath Ramachandran
    •  & Alessio Ciulli
  • Article
    | Open Access

    Injectable hydrogels have gained significant interest; yet, due to high viscosity, many are unsuitable for catheter delivery. Here, the authors report on cyclic peptides with low viscosity for catheter delivery, which form self-assembled peptide hydrogels following enzymatic cleavage and demonstrated delivery in vivo.

    • Andrea S. Carlini
    • , Roberto Gaetani
    •  & Nathan C. Gianneschi
  • Article
    | Open Access

    The peptide hormone GLP-1 has the potential to be a remedy for diabetes type II, yet is unstable. Here, the authors synthesized α-peptide-oligourea hybrid analogues of GLP-1 some of which showing significantly prolonged activity in vivo.

    • Juliette Fremaux
    • , Claire Venin
    •  & Sébastien R. Goudreau
  • Article
    | Open Access

    The selective formation of protein bioconjugates under physiological conditions is a challenging task. Here, the authors report that 1,4-dinitroimidazoles are reagents of choice for protein bioconjugation at either cysteine or lysine sites within short times and provide facile access to peptide macrocycles.

    • Qunfeng Luo
    • , Youqi Tao
    •  & Huan Wang
  • Article
    | Open Access

    Ring-opening polymerizations of α-amino acid N-carboxyanhydrides to form polypeptides are usually sensitive to moisture, slow and can undergo side reactions. Here the authors use lithium hexamethyldisilazide to initiate α-amino acid N-carboxyanhydride polymerizations that is very fast and can be conducted in an open vessel.

    • Yueming Wu
    • , Danfeng Zhang
    •  & Runhui Liu