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| Open AccessA conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1
SARM1 is a key player in axon degeneration. Here, the authors generate a nanobody, which specifically recognizes the NMN-bound state of SARM1 and helps resolve the SARM1 structure in an intermediate state of activation.
- Yun Nan Hou
- , Yang Cai
- & Yong Juan Zhao
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Article
| Open AccessInhibition of SRP-dependent protein secretion by the bacterial alarmone (p)ppGpp
Bacterial responses to nutrient limitation and other stress conditions are often modulated by the nucleotide-based second messenger (p)ppGpp. Here, the authors show that (p)ppGpp inhibits the SRP membrane-protein insertion and secretion pathway by binding to GTPases Ffh and FtsY.
- Laura Czech
- , Christopher-Nils Mais
- & Gert Bange
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Article
| Open AccessStructural basis of adenylyl cyclase 9 activation
Adenylyl cyclases (ACs) generate the second messenger cAMP and play an important role in cellular signaling. Here, the authors use cryo-EM to trace the conformational changes resulting from binding to partial and full activators to one of these enzymes, AC9.
- Chao Qi
- , Pia Lavriha
- & Volodymyr M. Korkhov
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| Open AccessMolecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger
Many bacterial cyclic-oligonucleotide-based antiphage signaling systems (CBASS) employ effectors with SAVED domains. Here, the authors present a biochemical and structural characterization of two such CBASS, providing mechanistic insights into bacterial antiphage defense.
- Shirin Fatma
- , Arpita Chakravarti
- & Raven H. Huang
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| Open AccessChemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate
Diadenosine polyphosphates (ApAs) are involved in cellular stress signaling but only a few molecular targets have been characterized so far. Here, the authors develop ApnA-based photoaffinity-labeling probes and use them to identify Ap3A and Ap4A binding proteins in human cell lysates.
- Lena Krüger
- , Christoph J. Albrecht
- & Andreas Marx
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Article
| Open AccessNucleotide proofreading functions by nematode RAD51 paralogs facilitate optimal RAD51 filament function
A RAD51 paralog complex, RFS-1/RIP-1, is shown to control ssDNA binding and dissociation by RAD-51 differentially in the presence and absence of nucleotide cofactors. These nucleotide proofreading activities drive a preferential accumulation of RAD-51-ssDNA complexes with optimal nucleotide content.
- Mário Špírek
- , Martin R. G. Taylor
- & Lumir Krejci
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Article
| Open AccessSugar phosphate activation of the stress sensor eIF2B
The activity of translation initiation factor eIF2B is known to be modulated through stress-responsive phosphorylation of its substrate eIF2. Here, the authors uncover the regulation of eIF2B by the binding of sugar phosphates, suggesting a link between nutrient status and the rate of protein synthesis.
- Qi Hao
- , Jin-Mi Heo
- & Carmela Sidrauski
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Article
| Open AccessBacterial cyclic diguanylate signaling networks sense temperature
Many bacteria use the second messenger cyclic diguanylate (c-di-GMP) to control motility, biofilm production and virulence. Here, the authors identify a thermosensitive enzyme that synthesizes c-di-GMP and modulates temperature-dependent motility, biofilm development and virulence in the opportunistic pathogen Pseudomonas aeruginosa.
- Henrik Almblad
- , Trevor E. Randall
- & Joe Jonathan Harrison
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Article
| Open AccessThe nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp
Nucleotides pppGpp and ppGpp regulate bacterial responses to nutritional and other stresses, while the potential roles of the related pGpp are unclear. Here, Yang et al. systematically identify proteins interacting with these nucleotides in Bacillus, and show that pGpp has roles distinct from those of (p)ppGpp.
- Jin Yang
- , Brent W. Anderson
- & Jue D. Wang
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Article
| Open AccessThe SecA motor generates mechanical force during protein translocation
The ATPase SecA drives Sec-dependent protein translocation across the bacterial plasma membrane. Here, the authors combine kinetic translocation measurements with single-molecule force spectroscopy and demonstrate that the SecA motor generates mechanical force to unfold and translocate preproteins.
- Riti Gupta
- , Dmitri Toptygin
- & Christian M. Kaiser
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Article
| Open AccessADP binding by the Culex quinquefasciatus mosquito D7 salivary protein enhances blood feeding on mammals
D7 proteins are highly abundant in the salivary glands of several blood feeding insects. Here, the authors study the ligand binding specificity and physiological roles of the mosquito D7 proteins CxD7L1 and CxD7L2, showing that CxD7L1 acquired ADP-binding properties to enhance blood feeding in mammals.
- Ines Martin-Martin
- , Andrew Paige
- & Eric Calvo
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Article
| Open AccessStructural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel
Opening of G protein-gated inwardly rectifying potassium channels (GIRK) is coupled to the activation of a GPCR. Here the authors use NMR and cell-based BRET assays to gain insights into the mechanisms underlying family-specific activation and find that pre-formation of the Gαi/oβγ-GIRK complex in the inactive state is responsible for specific GIRK activation and present a structural model for the Gαi/oβγ-GIRK complex.
- Hanaho Kano
- , Yuki Toyama
- & Ichio Shimada
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Article
| Open AccessProteome-wide solubility and thermal stability profiling reveals distinct regulatory roles for ATP
ATP can function as a biological hydrotrope, but its global effects on protein solubility have not yet been characterized. Here, the authors quantify the effect of ATP on the thermal stability and solubility of the cellular proteome, providing insights into protein solubility regulation by ATP.
- Sindhuja Sridharan
- , Nils Kurzawa
- & Mikhail M. Savitski
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| Open AccessNeuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms
Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.
- Christopher H. Douse
- , Stuart Bloor
- & Yorgo Modis
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| Open AccessThe SAM domain of mouse SAMHD1 is critical for its activation and regulation
The sterile alpha-motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that blocks HIV-1 infection by depleting cellular dNTPs. Here the authors present the structures of full-length mouse SAMHD1 in different nucleotide bound states and give insights into SAMHD1 activity regulation.
- Olga Buzovetsky
- , Chenxiang Tang
- & Yong Xiong
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| Open AccessCryo-EM structures of the ATP-bound Vps4E233Q hexamer and its complex with Vta1 at near-atomic resolution
The ESCRT-III and Vps4 complexes mediate a variety of membrane remodelling events. Here the authors describe the structure of the Vps4 hexamer complexed to its cofactor Vta1, and show that Vta1 bridges adjacent Vps4 subunits to promote formation of the active hexamer during ESCRT-III filament disassembly.
- Shan Sun
- , Lin Li
- & Sen-Fang Sui
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Article
| Open AccessDynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses
Heterotrimeric guanine-nucleotide-binding proteins (G proteins) act as molecular switches. Here the authors use NMR relaxation analyses, which reveal the dynamics of G protein alpha subunit binding to GDP on a microsecond timescale.
- Yuki Toyama
- , Hanaho Kano
- & Ichio Shimada
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Article
| Open AccessQuantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
The AAA+ ATPase p97 is an essential hexameric protein with multiple protein interaction partners and cellular functions. Here, the authors use interaction mapping to examine partner proteins of this large complex, and assess the effects of these proteins on the disassembly of the p97 complex.
- Anup Arumughan
- , Yvette Roske
- & Erich E. Wanker
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| Open AccessCrystal structures of the human elongation factor eEFSec suggest a non-canonical mechanism for selenocysteine incorporation
Specialized translation elongation factors (eEFSec and SelB) promote selenocysteine incorporation into proteins. Here, the authors report the structure of human eEFSec, examine its interactions with guanine nucleotides, and propose a non-canonical mechanism for decoding selenocysteine.
- Malgorzata Dobosz-Bartoszek
- , Mark H. Pinkerton
- & Miljan Simonović
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| Open AccessThe Arabidopsis acetylated histone-binding protein BRAT1 forms a complex with BRP1 and prevents transcriptional silencing
Transposons and repetitive sequences are typically subject to transcription silencing. Here, Zhang et al. find that the bromodomain-containing protein BRAT1 forms a complex with BRP1, recognizes histone acetylation and acts to prevent transcriptional silencing in Arabidopsis.
- Cui-Jun Zhang
- , Xiao-Mei Hou
- & Xin-Jian He
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| Open AccessStructural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer
Spiegelmers are mirror-image oligonucleotide aptamers designed for therapeutic use. Here the authors describe the crystal structure of the mixed L-RNA/L-DNA Spiegelmer NOX-D20 bound to complement component C5a, a key mediator of the innate immune response and clinical target in acute and chronic inflammatory disorders.
- Laure Yatime
- , Christian Maasch
- & Axel Vater