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Signaling by a bacterial phytochrome histidine kinase involves a conformational cascade reorganizing the dimeric photoreceptor
We present near complete cryo-EM structures of the dark and light-activated states of a bacterial phytochrome kinase to reveal how these photoreceptors translate light absorption into conformational changes that impact transmitter kinase cascades.
- E. Sethe Burgie
- , Katherine Basore
- & Richard D. Vierstra
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| Open Access
The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes
Eastern equine encephalitis virus (EEEV) uses the very low-density lipoprotein receptor (VLDLR) to infect cells of different species. This study finds that the ecto LA repeats of VLDLR binds EEEV at three distinct sites, generating multiple different binding modes that facilitate the cross-species transmission of EEEV.
- Duanfang Cao
- , Bingting Ma
- & Ye Xiang
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Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly
This study reports the cryo-EM structure of full-length MICAL1 in its autoinhibited conformation, unveiling the molecular mechanisms of tail-mediated inhibition and Rab-binding-mediated relief that regulate MICAL’s activity in F-actin disassembly.
- Leishu Lin
- , Jiayuan Dong
- & Zhiyi Wei
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Cryo-EM structure of the CDK2-cyclin A-CDC25A complex
CDC25 phosphatases are attractive anticancer drug targets that regulate CDK activity. Here, the authors present the cryo-EM structure of the CDK2-cyclin A-CDC25A complex at 2.7 Å resolution, detailing key protein-protein interactions.
- Rhianna J. Rowland
- , Svitlana Korolchuk
- & Jane A. Endicott
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Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation
DIM2-mediated DNA methylation contributes to heterochromatin formation in Neurospora. This study identifies that HP1 protein and the H3K9me3 mark synergistically control DIM2 activity, providing a mechanism for heterochromatin-guided DNA methylation.
- Zengyu Shao
- , Jiuwei Lu
- & Jikui Song
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Structural basis for the distinct core-antenna assembly of cryptophyte photosystem II
Structure of PSII-CAC from cryptophyte Rhodomonas salina reveals a distinct organization of CACs and the presence of CAL-II, which may play a critical role in stabilizing the dimeric PSII-CAC complex under stress conditions.
- Long Si
- , Shumeng Zhang
- & Mei Li
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Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in the 40S small ribosomal subunit
Tumor suppressor protein Pdcd4 is downregulated in tumor cells, whereas global mRNA translation within these cells is upregulated. Here, the authors determined the structure of human Pdcd4 bound to the ribosome, revealing how it blocks translation.
- Jailson Brito Querido
- , Masaaki Sokabe
- & Christopher S. Fraser
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Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger
The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical. Here, authors determined the structures of wildtype and disease-causing I607T mutant of ClC-3 in the apo and adenine nucleotides bounded states, which lays the structural basis of adenine nucleotides regulation in ClC-3.
- Yangzhuoqun Wan
- , Shuangshuang Guo
- & Fan Yang
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Metal ions guide the production of silkworm silk fibers
Silk fibers’ unique properties make them desirable for various applications. However, no synthetic method has reproduced this tough biomaterial due to poor understanding of their complex formation mechanism. Here, the authors map the natural composition of metal ions that guide the protein structural transformations during the fiber’s spinning process.
- Ori Brookstein
- , Eyal Shimoni
- & Ulyana Shimanovich
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Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase
Here, Bulvas et al use biochemical and cryo-EM techniques to profile the regulatory mechanisms of the essential mycobacterial enzyme IMPDH. They show how GTP and (p)ppGpp nucleotides inhibit IMPDH by locking it in an inactive state.
- Ondřej Bulvas
- , Zdeněk Knejzlík
- & Iva Pichová
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Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore
Using cryogenic electron microscopy, Gao et al. uncovered how CFTRInh-172 inhibits CFTR function by binding in its pore and allosterically inhibiting its gating. Their findings could pave the way for structure-based drug design for the treatment of secretory diarrhea and polycystic kidney disease.
- Xiaolong Gao
- , Han-I Yeh
- & Tzyh-Chang Hwang
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Structural basis of TRPV1 inhibition by SAF312 and cholesterol
SAF312 shows potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, authors show mechanistic insights into the regulation of TRPV1 by SAF312 and cholesterol.
- Junping Fan
- , Han Ke
- & Xiaoguang Lei
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High-affinity agonism at the P2X7 receptor is mediated by three residues outside the orthosteric pocket
The P2X7 receptor is an ATP-gated ion channel that mediates inflammasome activation. Here, authors report the structure of P2X7 bound to high-affinity agonist, BzATP, providing a framework to develop small molecules applicable to cancer biology.
- Adam C. Oken
- , Nicolas E. Lisi
- & Steven E. Mansoor
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Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain
DXPS is an important enzyme for isoprenoid synthesis in Plasmodium falciparum. Here, authors elucidate the cryo-EM structure of PfDXPS showing an N-terminal domain only present in this genus. Mutation studies show its importance in DXPS stability and activity.
- Victor O. Gawriljuk
- , Andre S. Godoy
- & Matthew R. Groves
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Bidirectional pilus processing in the Tad pilus system motor CpaF
The ATPase CpaF from C. crescentus powers pilus dynamics in the bacterial Tad pilus system. Cryo-EM and light microscopy characterisation of CpaF uncovers a mechanism for how CpaF may drive both pilus extension and retraction.
- Michael Hohl
- , Emma J. Banks
- & Harry H. Low
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A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state
Many neurotransmitters act on receptors coupled to GTP-binding G proteins. Here authors report the structure and activity of a mutant that locks the nucleotide-free and receptor-bound state of the G protein, leading to a rare neurological disorder.
- Kevin M. Knight
- , Brian E. Krumm
- & Henrik G. Dohlman
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Structural basis of the obligatory exchange mode of human neutral amino acid transporter ASCT2
ASCT2 is a Na+-dependent obligatory amino acid exchanger. Here, the authors untangle the structural basis of the exchange mechanism in ASCT2, revealing that structural rigidity and a high-affinity Na+ binding site effectively confine ASCT2 to an exchange mode.
- Anna M. Borowska
- , Maria Gabriella Chiariello
- & Dirk J. Slotboom
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The unique allosteric property of crocodilian haemoglobin elucidated by cryo-EM
Crocodilians are ambush predators that possess haemoglobin with an allosteric switch between R (high oxygen affinity) and T (low oxygen affinity) forms strongly controlled by bicarbonate ions, a unique evolutionary feature that helps the animal to stay underwater for extended periods of time.
- Katsuya Takahashi
- , Yongchan Lee
- & Jeremy R. H. Tame
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Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages
Here, the authors present the 3.5-Å-resolution cryo-EM structure of the jumbo phage ΦKZ capsid, revealing ten minor capsid proteins that are hypothesized to contribute to capsid assembly and stabilization.
- Yashan Yang
- , Qianqian Shao
- & Qianglin Fang
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Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding
It is common to engineer membrane proteins for cryo-EM analysis. Here, the authors report a cryo-EM structure of an engineered, functional VMAT2 with a non-canonical fold. Caution is advised when interpreting engineered membrane protein structures.
- Ying Lyu
- , Chunting Fu
- & Xiaoming Zhou
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Structural basis for VLDLR recognition by eastern equine encephalitis virus
Alphaviruses include several important human pathogens with outbreak potential. Here, the authors found that eastern equine encephalitis virus and Semliki Forest virus use distinct surfaces on their spike proteins to bind their shared receptor, VLDLR.
- Pan Yang
- , Wanyu Li
- & Jonathan Abraham
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MEILB2-BRME1 forms a V-shaped DNA clamp upon BRCA2-binding in meiotic recombination
MEILB2-BRME1 is a BRCA2-binding complex that is required for meiotic recombination. Here, the authors report the structure and DNA-binding of MEILB2-BRME1, revealing how its BRCA2-induced dimerization forms a V-shaped assembly that may clamp together DNA molecules to facilitate recombination.
- Manickam Gurusaran
- , Jingjing Zhang
- & Owen R. Davies
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Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization
The metabotropic glutamate receptors (mGluRs) are neuromodulator class C GPCRs. Here, authors characterize ligand-evoked activation and internalization of mGluRs to reveal bias in signaling and motivate structural determination of activation pathway intermediate states.
- Alexa Strauss
- , Alberto J. Gonzalez-Hernandez
- & Joshua Levitz
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Elucidating the Architectural dynamics of MuB filaments in bacteriophage Mu DNA transposition
Here, Zhao et al. use cryo-EM to show how MuB forms helical filaments around DNA. These structures play a crucial role in target DNA selection and transposition, shedding light on MuB’s functional mechanism.
- Xiaolong Zhao
- , Yongxiang Gao
- & Shanshan Li
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Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport
In this work, the authors present structural and functional evidence of lipid exchange within the gram-negative Mla pathway, broadening our understanding of lipid transport in bacteria and providing insight into the mechanism of a unique ABC transporter.
- Peter Wotherspoon
- , Hannah Johnston
- & Timothy J. Knowles
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Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis
Here the authors report the cryo-EM structure of heart-derived fibrils of an AL amyloidosis patient. Surprisingly, the fibrils form helical superstructures with collagen VI, potentially signifying a distinct pathophysiological mechanism for amyloidoses.
- Tim Schulte
- , Antonio Chaves-Sanjuan
- & Stefano Ricagno
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Oligomerization and a distinct tRNA-binding loop are important regulators of human arginyl-transferase function
ATE1 is an essential gene in mammals and is recognized as a master regulator of cells. Here, the authors describe structural insights into human ATE1, revealing mechanisms that regulate arginylation activity in cells.
- Xin Lan
- , Wei Huang
- & Yi Zhang
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Molecular basis for the activation of human spliceosome
Here, the authors have captured the intermediate states of the human spliceosome during its activation through cryo-EM reconstruction of six distinct spliceosomal complexes.
- Xiechao Zhan
- , Yichen Lu
- & Yigong Shi
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Structure of the red-shifted Fittonia albivenis photosystem I
Fittonia albivenis is shade-adapted ornamental plant that can efficiently use far-red light for photosynthesis. Here the authors describe the structure of the red-shifted F. albivenis photosystem I to give insights into how plants can use far-red light to drive photochemistry.
- Xiuxiu Li
- , Guoqiang Huang
- & Xiaochun Qin
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Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet
The MARTX toxins secreted by clinical V. vulnificus strains release the DUF1-RID effector duet in infected host cells. Here, the authors show that the duet hijacks calmodulin and Rac1, respectively, and transforms into a potent weapon to promote sepsis.
- Sanghyeon Choi
- , Youngjin Lee
- & Myung Hee Kim
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The structural basis of the activation and inhibition of DSR2 NADase by phage proteins
This research shows how the bacterial protein DSR2, which protects against phage infection by degrading NAD+, is activated by phage protein TTP and inhibited by phage protein DSAD1 through cryo-EM studies and biochemical assays.
- Ruiwen Wang
- , Qi Xu
- & Faxiang Li
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| Open Access
Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction
DNMT3A-nucleosome interaction underpins the genomic DNA methylation landscape. Here, the authors investigate how an N-terminal fragment of DNMT3A recognizes the H2AK119ub1-marked nucleosome, providing insights into the chromatin-targeting mechanism of DNMT3A.
- Xinyi Chen
- , Yiran Guo
- & Jikui Song
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The structural insight into the functional modulation of human anion exchanger 3
This study provides structural insights into human AE3’s role in pH regulation in excitable tissues, highlighting its structural differences from AE2 in anion transport regulation and their sensitivity to inhibitors.
- Liyan Jian
- , Qing Zhang
- & Yu Cao
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CryoET reveals actin filaments within platelet microtubules
Using focused ion beam milling and cryoelectron tomography, Tsuji et al. found actin filaments, with both cofilin-bound and canonical morphologies, within the lumen of human platelet microtubules and reconstituted these structures in vitro.
- Chisato Tsuji
- , Marston Bradshaw
- & Mark P. Dodding
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Assembly of respiratory syncytial virus matrix protein lattice and its coordination with fusion glycoprotein trimers
Here the authors use cryo-electron tomography and sub-tomogram averaging to determine the molecular organization of RSV. The structures show that the matrix (M) protein packs as a helical-like lattice and the F glycoprotein is present as anti-parallel pairs of trimers and coordinates with the M lattice.
- Bryan S. Sibert
- , Joseph Y. Kim
- & Elizabeth R. Wright
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GolpHCat (TMEM87A), a unique voltage-dependent cation channel in Golgi apparatus, contributes to Golgi-pH maintenance and hippocampus-dependent memory
Impaired ion channels regulating Golgi pH may cause altered Golgi morphology. Here authors identify TMEM87A as a pH-regulation cation channel expressed in astrocytes and neurons and determine the cryo-EM structure to understand the ion permeation pathway.
- Hyunji Kang
- , Ah-reum Han
- & C. Justin Lee
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Molecular and structural basis of the chromatin remodeling activity by Arabidopsis DDM1
Osakabe and colleagues report the cryo-EM structures of Arabidopsis nucleosomes and how they complex with the chromatin remodeler DDM1, providing insights into how DDM1 promotes the access of chromatin writers to heterochromatin.
- Akihisa Osakabe
- , Yoshimasa Takizawa
- & Hitoshi Kurumizaka
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Perturbed N-glycosylation of Halobacterium salinarum archaellum filaments leads to filament bundling and compromised cell motility
The archaellum, or archaeal ‘flagellum’, includes asparagine-linked glycans that are important for efficient cell motility in archaea through unclear mechanisms. Here, the authors show that glycan truncation leads to clustering of filaments and alterations in cell motility, suggesting that the glycans minimize archaellum filament aggregation that compromises cell motility.
- Shahar Sofer
- , Zlata Vershinin
- & Iris Grossman-Haham
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SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain
The authors report the structural basis of site-one protease (S1P) activation by SREBP regulating gene (SPRING). They show that SPRING displaces the inhibitory pro-domain of S1P, enabling S1P to cleave its canonical substrate SREBP2.
- Sebastian Hendrix
- , Vincent Dartigue
- & Daniel L. Kober
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| Open Access
GTPBP8 plays a role in mitoribosome formation in human mitochondria
Multiple GTP-binding proteins (GTPBPs) aid ribosome maturation. Here, authors pinpoint GTPBP8’s involvement in human mitoribosome maturation, demonstrating its specific binding to mitoribosomal large subunit RNA, which is necessary for ribosome assembly and protein synthesis.
- Miriam Cipullo
- , Genís Valentín Gesé
- & Joanna Rorbach
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| Open Access
Flotillin-mediated stabilization of unfolded proteins in bacterial membrane microdomains
The function of many bacterial processes depends on the formation of functional membrane microdomains (FMMs), which resemble the lipid rafts of eukaryotic cells. Here, Ukleja et al. show that FMMs mediate ATP-independent stabilization of unfolded proteins, which is essential for bacterial viability under cellular stress and during infection.
- Marta Ukleja
- , Lara Kricks
- & Daniel Lopez
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| Open Access
Cryo-EM unveils kinesin KIF1A’s processivity mechanism and the impact of its pathogenic variant P305L
Benoit et al. present high-resolution structures of dimeric microtubule-bound KIF1A, including its pathogenic P305L mutant. Their findings provide insights into KIF1A’s motility mechanism and potential therapies for associated neurological disorders.
- Matthieu P. M. H. Benoit
- , Lu Rao
- & Hernando Sosa
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| Open Access
Accurate Prediction of Protein Structural Flexibility by Deep Learning Integrating Intricate Atomic Structures and Cryo-EM Density Information
Cryo-EM is an experimental technique for uncovering protein structural and dynamic properties. Here, authors propose a neural network model to infer the structural flexibility of proteins from cryo-EM, demonstrating high accuracy and efficiency.
- Xintao Song
- , Lei Bao
- & Renmin Han
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| Open Access
Dimeric transport mechanism of human vitamin C transporter SVCT1
Vitamin C is an essential nutrient for our daily life, but how it is transported into our bodies remained unclear. Here, authors revealed multiple structures of human vitamin C transporter, providing insights into its molecular mechanisms.
- Takaaki A. Kobayashi
- , Hiroto Shimada
- & Osamu Nureki
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| Open Access
Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2
The SIT1-ACE2 complex transports the amino acid proline and is the receptor of SARS-CoV-2. Here, the authors identify specific sequence requirements for proline transport and explain for how a missense mutation causes iminoglycinuria.
- Huanyu Z. Li
- , Ashley C. W. Pike
- & David B. Sauer
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| Open Access
De novo atomic protein structure modeling for cryoEM density maps using 3D transformer and HMM
Here the authors report Cryo2Struct which can automatically build accurate atomic protein structures from cryo-EM density maps using artificial intelligence: it also provides residue-wise confidence scores for the modeled structures.
- Nabin Giri
- & Jianlin Cheng
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| Open Access
Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline
Tigecycline is widely used to treat complex bacterial infections. Here, authors present cryo-EM structures of tigecycline-bound eukaryotic ribosomes, revealing how it also targets the human mitoribosome with distinct binding properties.
- Xiang Li
- , Mengjiao Wang
- & Jingdong Cheng
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| Open Access
A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines
Evolution of viruses undermines the efficacy of vaccines and antibody therapies. To overcome this challenge, authors describe a strategy for prefusion-stabilization to provide proof-of-principle for fusion-machinery sarbecovirus vaccines.
- Jimin Lee
- , Cameron Stewart
- & David Veesler
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| Open Access
Structural basis for potent neutralization of human respirovirus type 3 by protective single-domain camelid antibodies
Respirovirus 3 is a major cause of respiratory infection. Here authors generate and explore heavy-chain antibody fragments that target the fusion protein and test these in vitro and in an animal model.
- Nicole V. Johnson
- , Revina C. van Scherpenzeel
- & Jason S. McLellan
Structural insights into the mechanism and dynamics of proteorhodopsin biogenesis and retinal scavenging