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| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz
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Article
| Open AccessLigand recognition and G protein coupling of the human itch receptor MRGPRX1
MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.
- Lulu Guo
- , Yumu Zhang
- & Jin-Peng Sun
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Article
| Open AccessStructural basis for negative regulation of the Escherichia coli maltose system
MalY represses the E. coli maltose system by direct interaction with MalT that blocks its oligomerization. Maltotriose-binding leads to conformational remodelling of MalT and stabilizes the C-terminal domains required for downstream signalling.
- Yuang Wu
- , Yue Sun
- & Jijie Chai
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Article
| Open AccessMolecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system
Chemokine receptors are G protein-coupled receptors (GPCRs) involved in immune responses and characterized by ligand promiscuity Here, the authors characterize signaling through chemokine receptors CXCR4 and CXCR7, with insights into intrinsic-bias encoded in the CXCR4-CXCR7 system.
- Parishmita Sarma
- , Carlo Marion C. Carino
- & Arun K. Shukla
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Article
| Open AccessA conserved membrane curvature-generating protein is crucial for autophagosome formation in fission yeast
Rop1 is the single representaive of a subfamily of the membrane-curvature generating REEPs in fission yeast. Wang et al. show that Rop1 is crucial for the macroautophagy of organelles and cytosolic proteins, facilitating autophagosome formation.
- Ning Wang
- , Yoko Shibata
- & Tom A. Rapoport
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Article
| Open AccessMolecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel
Mrs2 is a mitochondrial Mg2+ channel that is essential for metabolic function. Here, the authors present cryo-EM structures of human Mrs2 revealing symmetrical pentameric assembly and how Mrs2 permeates Mg2+.
- Ming Li
- , Yang Li
- & Yuequan Shen
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Article
| Open AccessBtuB TonB-dependent transporters and BtuG surface lipoproteins form stable complexes for vitamin B12 uptake in gut Bacteroides
Uptake of vitamin B12 is important for colonisation of the gut by Bacteroides species. Here the authors characterise B12 uptake in Bacteroides thetaiotaomicron, mediated by outer membrane protein complexes consisting of surface-exposed BtuG lipoproteins and BtuB TonB-dependent transporters.
- Javier Abellon-Ruiz
- , Kalyanashis Jana
- & Bert van den Berg
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Article
| Open AccessControl of motor landing and processivity by the CAP-Gly domain in the KIF13B tail
Intracellular transport of material along microtubules by kinesin motors is critical for cellular homeostasis. Here the authors uncover a unique role for a specialized kinesin tail domain in directing motor transport along specific microtubule tracks.
- Xiangyu Fan
- & Richard J. McKenney
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Article
| Open AccessMembrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.
- Bharat Poudel
- , Rajitha Rajeshwar T
- & Juan M. Vanegas
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Article
| Open AccessThe AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming
This study demonstrates that an evolutionary conserved, autoregulatory ‘AT-hook’ domain of SWI/SNF regulates gene transcription and enhancer activation by modulating SWI/SNF intrinsic catalytic activity and is critical for cell lineage priming.
- Dhurjhoti Saha
- , Solomon Hailu
- & Blaine Bartholomew
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Article
| Open AccessThe Ycf48 accessory factor occupies the site of the oxygen-evolving manganese cluster during photosystem II biogenesis
The Ycf48 accessory factor is important for the assembly and repair of the photosystem II (PSII) complex of oxygenic photosynthesis. Here, the authors show that Ycf48 occupies the binding site of the oxygen evolving Mn cluster early in PSII biogenesis.
- Ziyu Zhao
- , Irene Vercellino
- & Josef Komenda
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Article
| Open AccessEnergetic robustness to large scale structural fluctuations in a photosynthetic supercomplex
Robust photosynthetic light harvesting occurs in large membrane supercomplexes. Here, the authors show that supercomplexes occupy an unexpectedly large range of conformations yet maintain their efficiency due to specific, critical chlorophylls.
- Dvir Harris
- , Hila Toporik
- & Yuval Mazor
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Article
| Open AccessPartition complex structure can arise from sliding and bridging of ParB dimers
In many bacteria and plasmids, DNA segregation is controlled by the ParABS system, an essential component of which is the formation of a nucleoprotein complex. Here, making use of recent discoveries, the authors develop a sliding and bridging model to predict the fine structure of this complex.
- Lara Connolley
- , Lucas Schnabel
- & Seán M. Murray
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Article
| Open AccessA ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development
The molecular mechanisms ensuring early face, brain, and skin formation are unclear. Here, the authors uncover a posttranslational pathway that controls cytoskeletal signaling circuits to coordinate ectodermal patterning and neurulation.
- Anthony J. Asmar
- , Shaun R. Abrams
- & Achim Werner
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Article
| Open AccessExpulsion mechanism of the substrate-translocating subunit in ECF transporters
The final step in an ECF transporters transport cycle involves the expulsion of the membrane embedded substrate binding protein (the S-component) from the motor (the ECF module). Here the authors show how the motor uses ATP binding to load a molecular spring, and adjusts the shape of the membrane, to achieve this step.
- Chancievan Thangaratnarajah
- , Mark Nijland
- & Dirk J. Slotboom
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Article
| Open AccessZinc-finger BED domains drive the formation of the active Hermes transpososome by asymmetric DNA binding
Hermes is a member of the eukaryotic hAT DNA transposon superfamily. Its transposase forms a ring-shaped tetramer of dimers to provide sufficient number of DNA binding BED domains to locate its transposon left-end in genomic DNA and facilitate the subsequent interaction with the right-end.
- Laurie Lannes
- , Christopher M. Furman
- & Fred Dyda
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Article
| Open AccessStructural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants
SARS-CoV-2 Omicron variant evolves into multiple sub-variants. Here, authors evaluate the binding capacity of these sub-variants to human and animal ACE2s and reveal molecular bases for their receptor binding and broader interspecies recognition.
- Zhennan Zhao
- , Yufeng Xie
- & Jianxun Qi
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Article
| Open AccessIdentification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1
The authors identify a small molecule inhibitor targeting the ssDNA-binding function of T. brucei Replication Protein A1 without affecting the host ortholog. They confirm the key residue in TbRPA1 involved in the species-specific selectivity of the chemical probe.
- Aditi Mukherjee
- , Zakir Hossain
- & Hee-Sook Kim
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Article
| Open AccessStructures of channelrhodopsin paralogs in peptidiscs explain their contrasting K+ and Na+ selectivities
Recently discovered kalium channelrhodopsins (KCRs) are optogenetic tools for neuronal silencing. Here, authors report cryo-electron microscopy structures of KCR1 from Hyphochytrium catenoides and a highly homologous but sodium-selective channel from the same organism.
- Takefumi Morizumi
- , Kyumhyuk Kim
- & Oliver P. Ernst
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Article
| Open AccessCharacterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
RNA-Binding Proteins (RBPs) are critical regulators of RNA biology. Here, the authors describe the Brain-pCLAP methodology, uncover the RBP atlas of the mouse brain and demonstrate the differential binding of the splicing factor RBM5 to Huntington’s disease relevant transcripts in R6/2 mice.
- Meeli Mullari
- , Nicolas Fossat
- & Michael L. Nielsen
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Article
| Open AccessGPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach
Selective GPCR-G protein complexes formation is critical for signal transduction regulation. Here, the authors use a data-driven approach to show that the structures of experimental and predicted complex interfaces inform, at least partially, on G protein binding preferences.
- Marin Matic
- , Pasquale Miglionico
- & Francesco Raimondi
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Article
| Open AccessArchitecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair
B12-dependent human methylmalonly-CoA mutase (MMUT) requires the chaperone MMAA. The authors report the crystal structure of MMUT-MMAA, which shows a MMAA-driven conformational change in MMUT involved n B12 loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations.
- Romila Mascarenhas
- , Markus Ruetz
- & Ruma Banerjee
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Article
| Open AccessStructures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity
The human tumor suppressor p53 interacts with the BCL-2 family proteins to regulate apoptosis. Here, the authors solve the structures of p53 in complex with the antiapoptotic protein BCL-2 and suggest a mechanism by which p53 promotes apoptosis by competitively antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family proteins.
- Hudie Wei
- , Haolan Wang
- & Yongheng Chen
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Article
| Open AccessCytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.
- Paul T. Morse
- , Gonzalo Pérez-Mejías
- & Maik Hüttemann
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Article
| Open AccessAtomic structure of a nudivirus occlusion body protein determined from a 70-year-old crystal sample
Viral occlusion bodies are robust protein crystals that encapsulate virions of some insect viruses. Here, the authors determine the nudivirus occlusion body structure and describe common principles of occlusion body structure.
- Jeremy R. Keown
- , Adam D. Crawshaw
- & Jonathan M. Grimes
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Article
| Open AccessExtending the dynamic range of biomarker quantification through molecular equalization
The human plasma proteome spans over 10 orders of magnitude, but current quantification methods cover only 3-4 orders. Here, authors propose a tuning approach for proximity-based assays, enabling simultaneous quantification of four analytes across a wide concentration range (low fM to mid-nM).
- Sharon S. Newman
- , Brandon D. Wilson
- & H. Tom Soh
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Article
| Open AccessCryo-EM structures of full-length integrin αIIbβ3 in native lipids
The structural basis of integrin signaling in health and disease is not fully understood. Here, the authors determine the cryoEM structure of full-length platelet integrin αIIbβ3 in its apo and eptifibatide-bound conformations in a native membrane environment.
- Brian D. Adair
- , Jian-Ping Xiong
- & M. Amin Arnaout
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Article
| Open AccessCytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr
The neuronal RNA-binding protein Ptbp2 is known to regulate neuronal differentiation by modulating alternative splicing. Here, the authors reveal an additional role of cytosolic Ptbp2, which regulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein hnRNP R.
- Saeede Salehi
- , Abdolhossein Zare
- & Michael Sendtner
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Article
| Open AccessMembranes prime the RapGEF EPAC1 to transduce cAMP signaling
EPAC1 is a cAMP-activated guanine nucleotide exchange factor (GEF) for Rap GTPases and a major transducer of cAMP signaling. Here, the authors show anionic membranes can activate EPAC1 independently of cAMP, increase its affinity for cAMP by two orders of magnitude, and synergize with cAMP to yield maximal GEF activity.
- Candice Sartre
- , François Peurois
- & Jacqueline Cherfils
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Comment
| Open AccessLimited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies
Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.
- Sara Weirich
- & Albert Jeltsch
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Article
| Open AccessStructural basis of CXC chemokine receptor 1 ligand binding and activation
Chemokines are small proteins secreted at sites of injury. Here, the authors describe the structure of the chemokine receptor CXCR1 bound to chemokine CXCL8, solved by cryo-EM. The model helps explain the ligand preferences of this receptor.
- Naito Ishimoto
- , Jae-Hyun Park
- & Sam-Yong Park
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Article
| Open AccessMechanism of ATP hydrolysis dependent rotation of bacterial ATP synthase
The ATP synthase FoF1 undergoes rotation in discrete 120° steps. Using cryo-EM analysis, the authors characterise intermediate structures within these 120° steps at 81°, 83°, 91°, and 101°. This shows that FoF1 undergoes a total of 15 steps in a 360° rotation, exhibiting multiple discreet movements per full rotation as opposed to one fluid motion.
- Atsuki Nakano
- , Jun-ichi Kishikawa
- & Ken Yokoyama
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Article
| Open AccessBioinspired one-pot furan-thiol-amine multicomponent reaction for making heterocycles and its applications
Homogeneous engineering of proteins is promising to study biological functions and for the development of therapeutic conjugates. Here, the authors report a one-pot multicomponent Furan-Thiol-Amine reaction for diverse applications, including labelling of peptides, synthesis of macrocyclic and stapled peptides, selective modification of different proteins with varying payloads, and labelling of lysine and cysteine in a complex human proteome.
- Yuwen Wang
- , Patrick Czabala
- & Monika Raj
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Article
| Open AccessATPase activity of DFCP1 controls selective autophagy
The endoplasmic reticulum protein DFCP1 is found on omegasomes implicated in autophagosome biogenesis, but its function has remained unknown. Here, Nähse et al. show that DFCP1 is an ATPase that mediates selective autophagy by promoting constriction of large omegasomes.
- Viola Nähse
- , Camilla Raiborg
- & Harald Stenmark
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Article
| Open AccessComplement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains
IgG3 antibodies have potent effector functions, but are not used as therapeutics and structural data are missing. Here, the authors combine cryoEM and MS to study IgG3-mediated complement activation to provide the first structural insights into IgG3.
- Leoni Abendstein
- , Douwe J. Dijkstra
- & Thomas H. Sharp
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Article
| Open AccessProfiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform
Interrogating the dynamic and functionally diverse signaling of GPCRs requires comprehensive cellular tools. Here Zeghal et al. develop Tango-Trio, a screening platform capable of profiling basal and drug-activated activities at hundreds of GPCRs.
- Manel Zeghal
- , Geneviève Laroche
- & Patrick M. Giguère
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Article
| Open AccessStructure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies
HCV vaccine development has been challenged by difficulties in the biochemical preparation of E1E2 ectodomains. Here, the authors structurally characterize an engineered soluble E1E2 ectodomain complexed with broadly neutralizing antibodies, revealing it adopts a native fold amenable for vaccine design.
- Matthew C. Metcalf
- , Benjamin M. Janus
- & Gilad Ofek
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Article
| Open AccessTargeted cross-linker delivery for the in situ mapping of protein conformations and interactions in mitochondria
Current methods for analysing protein structures and interactions generally require the separation of specific organelles or changes to the intracellular environment. Here, authors developed nanocarrier-based cross-linking mass spectrometry techniques to assess mitochondrial proteins within living cells.
- Yuwan Chen
- , Wen Zhou
- & Yukui Zhang
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Article
| Open AccessStructural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome
The Wnt enhanceosome is responsible for the transactivation of Wnt target genes in response to stimulation of cells by extracellular Wnt signals. Here, Wang et al. show BCL9, Pygo, LDB1 and SSBP form a stable core complex within the Wnt enhanceosome. Furthermore, they determine the crystal structure of the Pygo2-LDB1-SSBP2 ternary complex, which provides a promising therapeutic target for blocking Wnt/β-catenin signaling in cancer.
- Hongyang Wang
- , Mariann Bienz
- & Wenqing Xu
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Article
| Open AccessStructural basis of protein condensation on microtubules underlying branching microtubule nucleation
TPX2 is a key factor stimulating branching microtubule (MT) nucleation. TPX2 forms condensates on MTs critical for branching. In this work, the authors report the atomic-level structure of TPX2 C-terminal minimal active domain on MT lattice and its binding interface, determined by magic-angle-spinning NMR.
- Changmiao Guo
- , Raymundo Alfaro-Aco
- & Tatyana Polenova
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Article
| Open AccessStructural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody
α1A-adrenergic receptor (α1AAR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α1AAR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.
- Yosuke Toyoda
- , Angqi Zhu
- & Xiangyu Liu
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Article
| Open AccessStructure and proposed DNA delivery mechanism of a marine roseophage
Tailed bacteriophages account for the majority of all phages. Here, the authors employ cryo-EM and structure prediction techniques to investigate the atomic structure of the R4C phage capsid and the in- situ structure of its unique long rigid tail.
- Yang Huang
- , Hui Sun
- & Ningshao Xia
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Article
| Open AccessStructural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity
The SID-1 family is a putative channel/transporter for transporting nucleic acids. Here, Qian et al. report the dimeric structure of human SIDT2 suggesting that it may act as a transporter but not a channel. In addition, it has a ceramidase activity.
- Dandan Qian
- , Ye Cong
- & Deshun Gong
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Article
| Open AccessCeramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis
The SPT-ORMDL complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here, the authors elucidate the molecular basis of ceramide sensing by the human SPTORMDL complex for establishing sphingolipid homeostasis.
- Tian Xie
- , Peng Liu
- & Xin Gong
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Article
| Open AccessMechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design
Myosin A (PfMyoA) is essential for the pathogenesis of Plasmodium falciparum, the causative agent of malaria. Here we decipher the mechanism by which a small molecule inhibitor (KNX-002) of PfMyoA impedes its motor activity.
- Dihia Moussaoui
- , James P. Robblee
- & Anne Houdusse
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Article
| Open AccessA 2.2 Å cryoEM structure of a quinol-dependent NO Reductase shows close similarity to respiratory oxidases
Quinol-dependent nitric oxide reductases, unique to bacteria, are considered members of respiratory heme copper oxidases. A 2.2 Å cryoEM structure of qNOR is reported shedding light on key aspects of enzyme mechanism including quinol binding and pathways for electron, substrate, and proton transport.
- Alex J. Flynn
- , Svetlana V. Antonyuk
- & S. Samar Hasnain
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Article
| Open AccessSubstrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.
- Shana Bergman
- , Rosemary J. Cater
- & George Khelashvili
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Article
| Open AccessStructural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
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Article
| Open AccessA crucial role for dynamic expression of components encoding the negative arm of the circadian clock
A screen for clock mutants uncovered a conserved novel auxiliary NuA4 histone acetylase complex, containing orthologs of BRD-8 and BYE-1, needed for maintaining the timely Negative Element expression required for sustaining a normal circadian rhythm.
- Bin Wang
- , Xiaoying Zhou
- & Jay C. Dunlap
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