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| Open AccessThe DUSP–Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange
Ubiquitin-specific protease USP4 regulates several cellular signalling pathways. Here, Clerici et al.show that the DUSP–Ubl domain of USP4 is required for full catalytic activity, by enhancing the release of ubiquitin from the catalytic site after substrate hydrolysis.
- Marcello Clerici
- , Mark P. A. Luna-Vargas
- & Titia K. Sixma
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Article
| Open AccessCiliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism
Polycystins (PC) 1 and 2 are large transmembrane proteins that play a vital role in the function of primary cilia. Here, Kim et al. identify the requirements for polycystin trafficking to the cilium, involving a PC1–PC2 interaction, PC1 proteolytic cleavage and a specific trafficking module at the trans-Golgi network.
- Hyunho Kim
- , Hangxue Xu
- & Feng Qian
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Article
| Open AccessCpG island-mediated global gene regulatory modes in mouse embryonic stem cells
CpG islands are high GC content DNA elements that surround the majority of transcriptional start sites in eukaryotes. Here, the authors analyse over 200 genomic data sets to provide new insight into global CpG islands-dependent regulatory mechanisms in differentiated and pluripotent stem cells.
- Samuel Beck
- , Bum-Kyu Lee
- & Jonghwan Kim
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Histone H3.3 and its proteolytically processed form drive a cellular senescence programme
Cellular senescence involves extensive structural changes to chromatin, but the role of histone variants and histone cleavage is unknown. Here, Duarte et al.identify histone variant H3.3 and its proteolytically processed form lacking a portion of the N-terminal tail as key regulators of senescence.
- Luis F. Duarte
- , Andrew R. J. Young
- & Emily Bernstein
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Versatile in vitro system to study translocation and functional integration of bacterial outer membrane proteins
The mechanisms of protein translocation across and integration into bacterial outer membranes are poorly understood. Here, Norell et al. reconstitute type-V secretion and β-barrel protein biogenesis in proteoliposomes providing a versatile cell-free system to study integration and translocation.
- Derrick Norell
- , Alexander Heuck
- & Enguo Fan
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Reconstitution of a nanomachine driving the assembly of proteins into bacterial outer membranes
The translocation and assembly module (TAM) is a nanomachine responsible for assembly of proteins into the outer membrane of pathogenic bacteria. Here, Shen et al.use magnetic contrast neutron reflectrometry to visualize movements within the TAM and insertion of a substrate protein into the lipid bilayer.
- Hsin-Hui Shen
- , Denisse L. Leyton
- & Trevor Lithgow
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Article |
Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy
Understanding the molecular basis of receptor activation requires characterizing the dynamic equilibrium of conformational states. Here the authors show that the metabotropic glutamate receptor oscillates between conformations on a sub-millisecond timescale, and agonists quantitatively shift the equilibrium towards the activated state based on their potency.
- Linnea Olofsson
- , Suren Felekyan
- & Emmanuel Margeat
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Article
| Open AccessLateral opening of the bacterial translocon on ribosome binding and signal peptide insertion
Integral membrane proteins laterally partition from the SecYEG translocon into the phospholipid bilayer. Here, the authors use photo-induced electron transfer to show that ribosome binding induces the opening of the lateral gate, and demonstrate that lateral opening does not happen at low temperature.
- Yan Ge
- , Albena Draycheva
- & Wolfgang Wintermeyer
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Constitutive phospholipid scramblase activity of a G protein-coupled receptor
Opsin has recently been shown to equilibrate phospholipids across the photoreceptor disc membranes. Goren et al.demonstrate that the large conformational changes driven by exposure to light are not required for this activity, and provide insight into the potential mechanisms of lipid translocation.
- Michael A. Goren
- , Takefumi Morizumi
- & Anant K. Menon
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Article
| Open AccessXTACC3–XMAP215 association reveals an asymmetric interaction promoting microtubule elongation
chTOG, a microtubule polymerase, interacts with TACC3 during mitosis to regulate spindle formation. By studying their Xenopus homologues, Mortuza et al. discover that one TACC3 recruits two chTOG molecules to the spindle, increasing its local concentration and promoting microtubule elongation.
- Gulnahar B. Mortuza
- , Tommaso Cavazza
- & Guillermo Montoya
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The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism
Myelination of peripheral axons by Schwann cells is essential for proper transmission of nerve signals but the underlying mechanisms are not completely understood. Here the authors show that metabolic changes are required to ensure Schwann cell differentiation and proper myelination, and involve the tumour suppressor Lkb1 in regulating this process.
- Shabnam Pooya
- , Xiaona Liu
- & Biplab Dasgupta
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Membrane curvature sensing by the C-terminal domain of complexin
Complexin binds to synaptic vesicles and inhibits spontaneous exocytosis. Here Snead et al. show that the high curvature of the vesicle membrane is important for membrane binding, and induces a conformational change that is important for complexin’s inhibitory function.
- David Snead
- , Rachel T. Wragg
- & David Eliezer
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Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity
Alpha-2-macroglobulins are protease inhibitors that function as part of eukaryotic innate immunity. Here, Wong and Dessen solve structures of Salmonella alpha-2-macroglobulin and show that it probably serves as part of a rudimentary bacterial immune system in a similar way to the eukaryotic counterpart.
- Steve G. Wong
- & Andréa Dessen
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A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment
Membrane curvature and lipid composition direct the binding of many peripheral membrane proteins. Here, Vanni et al. use a combination of in vitroand molecular dynamics approaches to quantify how lipid-packing defects in membranes of various composition and curvature dictate the membrane adsorption of a model lipid-binding protein.
- Stefano Vanni
- , Hisaaki Hirose
- & Romain Gautier
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Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway
The crystal structure of the A2A GPCR suggested that water molecules might form a continuous pathway that becomes disrupted during receptor activation. Here Yuan et al.instead show that a conserved layer of hydrophobic residues forms a gate that opens to form a continuous water channel upon receptor activation.
- Shuguang Yuan
- , Slawomir Filipek
- & Horst Vogel
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Article
| Open AccessDivision of labour between Myc and G1 cyclins in cell cycle commitment and pace control
The transcription factor E2F is critical for determining cell proliferation. By monitoring E2F activity in single cells throughout the cell cycle, Dong et al.provide evidence that Myc and G1 cyclin/CDKs regulate different aspects of E2F temporal dynamics, resulting in distinct phenotypic outputs.
- Peng Dong
- , Manoj V. Maddali
- & Lingchong You
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Protein crystalline frameworks with controllable interpenetration directed by dual supramolecular interactions
Proteins are particularly desirable building blocks for self-assembled biomimetic materials. Here, the authors present crystalline frameworks based on concanavalin A with controllable levels of interpenetration via dual supramolecular interactions.
- Fuji Sakai
- , Guang Yang
- & Ming Jiang
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Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions
Several recent studies suggest that telomerase has key physiologic functions beyond its well-known role telomere maintenance. Here, Garcia Gonzalez et al. implicate telomerase in the regulation of ribosomal DNA transcription by RNA polymerase I.
- Omar Garcia Gonzalez
- , Robin Assfalg
- & Sebastian Iben
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Gαs regulates the post-endocytic sorting of G protein-coupled receptors
Following their internalization, G protein-coupled receptors may continue to signal from endosomes through downstream proteins such as Gαs. Rosciglione et al. reveal that Gαsalso regulates the onward trafficking of these receptors from endosomes to lysosomes by interacting with components of the ESCRT complex.
- Stéphanie Rosciglione
- , Caroline Thériault
- & Christine Lavoie
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Article
| Open AccessLigand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1
G-protein coupled receptors can signal through G-proteins or through β-arrestin, however mechanisms determining pathway selection remain unclear. Here the authors show that the duration of cannabinoid receptor clustering in clathrin coated pits prior to endocytosis determines the strength of β-arrestin signalling.
- Jacqueline Flores-Otero
- , Kwang H. Ahn
- & Guillermo A. Yudowski
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Filamin acts as a key regulator in epithelial defence against transformed cells
Mutations resulting in cell transformation occur in single cells to begin with and these cells can be eliminated from epithelial layers. Here, the authors describe a mechanism whereby neighbouring normal cells mediate this extrusion using filamin and intermediate filament, vimentin.
- Mihoko Kajita
- , Kaoru Sugimura
- & Yasuyuki Fujita
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Cementing proteins provide extra mechanical stabilization to viral cages
Some viruses possess ‘decoration’ proteins, such as gpD in lambda phage, that stabilize the viral particles in poorly understood ways. Here the authors show that gpD incorporation into lambda particles provides mechanical reinforcement and increased resistance to punctual deformations and collisions.
- M. Hernando-Pérez
- , S. Lambert
- & P. J. de Pablo
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Direct optical sensing of single unlabelled proteins and super-resolution imaging of their binding sites
The development of biosensors with improved sensitivity for the detection of biological molecules presents obvious possibilities for improved diagnostic tools in healthcare. Here, the authors present a technique for the label-free detection and super-resolution imaging of single proteins.
- Marek Piliarik
- & Vahid Sandoghdar
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Article
| Open AccessMulti-protein assemblies underlie the mesoscale organization of the plasma membrane
Although many proteins adopt uneven distributions in the plasma membrane, it is not clear how these nanoscale heterogeneities relate to the general protein patterning of the membrane. Saka et al. use click chemistry to reveal the mesoscale organization of membrane proteins into multi-protein assemblies.
- Sinem K. Saka
- , Alf Honigmann
- & Silvio O. Rizzoli
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Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A
As chromosomes align during metaphase, they initially oscillate back and forth before settling at the metaphase plate. Häfner et al. show that antagonistic phosphorylation and dephosphorylation of the kinesin Kif18A underlies this behaviour and is required for accurate sister chromatid segregation.
- Julia Häfner
- , Monika I. Mayr
- & Thomas U. Mayer
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Single-molecule analysis of transcription factor binding at transcription sites in live cells
Despite numerous previous studies, the nature of the interaction of transcription factors (TF) with their endogenous response elements (REs) has remained unclear. Here the authors characterize the binding of p53 and glucocorticoid receptor to their endogenous REs and find that transcriptionally productive interactions are transient and involve only a small fraction of cellular TF molecules.
- Tatsuya Morisaki
- , Waltraud G. Müller
- & James G. McNally
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Article |
A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells
PTEN is a prominent tumour suppressor and monitoring its conformation and activity are key to developing targeted therapies. Here, the authors develop a bioluminescence resonance energy transfer biosensor for PTEN conformation and identify novel G protein-coupled receptor regulation and therapeutic activation.
- Evelyne Lima-Fernandes
- , Stanislas Misticone
- & Mark G.H. Scott
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Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators
The haemogenic endothelium gives rise to haematopoietic cells including haematopoietic stem cells. Here, the authors show that the transduction of two combinations of transcription factors into human pluripotent stem cells convert these into haemogenic endothelial cells with distinct lineage potentials.
- Irina Elcheva
- , Vera Brok-Volchanskaya
- & Igor Slukvin
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Article |
Conserved architecture of the core RNA polymerase II initiation complex
It was suggested that despite the conservation of their components, yeast and human pol II initiation complexes diverged in architecture. Mühlbacher et al.now demonstrate that the yeast and human core complexes are structurally conserved and provide insight into the conformations adopted by TFIIF during initiation.
- Wolfgang Mühlbacher
- , Sarah Sainsbury
- & Patrick Cramer
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SNARE-fusion mediated insertion of membrane proteins into native and artificial membranes
The study of cell membrane proteins can be simplified by incorporating them into lipid bilayers, but doing this for multiple proteins can be challenging. Here, the authors present a technique to achieve this, and show reconstitution of a bacterial respiratory chain from individual components.
- Gustav Nordlund
- , Peter Brzezinski
- & Christoph von Ballmoos
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DSIF and NELF interact with Integrator to specify the correct post-transcriptional fate of snRNA genes
The elongation factors DSIF and NELF have established roles in polymerase pausing, elongation and 3'-end processing of replication-dependent histone mRNAs. Here the authors demonstrate that DSIF and NELF form a complex with Integrator and allow proper 3'-processing of snRNA transcripts by preventing the recruitment of CstF.
- Junichi Yamamoto
- , Yuri Hagiwara
- & Yuki Yamaguchi
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Article
| Open AccessVisualizing active membrane protein complexes by electron cryotomography
Few tools are available to identify active membrane proteins within their native lipid environment. Here, Gold et al. report on a strategy that can be used for site-specific labelling of membrane proteins via electron cryotomography.
- Vicki A.M. Gold
- , Raffaele Ieva
- & Werner Kühlbrandt
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The palindromic DNA-bound USP/EcR nuclear receptor adopts an asymmetric organization with allosteric domain positioning
Nuclear receptors use DNA- and ligand-binding to regulate gene expression. Here, Maletta et al. report the first structural description of a full inverted repeat-bound nuclear receptor complex, which shows that the protein structure is asymmetric, despite the symmetry of the bound DNA.
- Massimiliano Maletta
- , Igor Orlov
- & Bruno P. Klaholz
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RNA-binding proteins regulate the expression of the immune activating ligand MICB
The expression of stress-induced ligands and their recognition by the NKG2D-activating receptor is important for the elimination of virally infected and cancerous cells by cytotoxic lymphocytes. Here, the authors provide insights into the post-transcriptional mechanism regulating the expression of the NKG2D ligand, MICB.
- Daphna Nachmani
- , Tony Gutschner
- & Ofer Mandelboim
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Correlated motions are a fundamental property of β-sheets
Functional changes in protein structures are involved in a large number of biochemical processes. Here, the authors perform a simulation study of known protein structures to show how β-sheets possess the ability to facilitate concerted backbone motions.
- R. Bryn Fenwick
- , Laura Orellana
- & Xavier Salvatella
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Visualization of a polytopic membrane protein during SecY-mediated membrane insertion
Membrane protein topogenesis is not fully understood, although the path that proteins take through the ribosome and Sec-complex has been described. Here, Bischoff et al.present the structure of a ribosome-SecY complex containing an intermediate of proteorhodopsin, which provides further insight into this topogenesis.
- Lukas Bischoff
- , Stephan Wickles
- & Roland Beckmann
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Singlet oxygen triplet energy transfer-based imaging technology for mapping protein–protein proximity in intact cells
Fluorescence imaging can be used for the characterization of protein interactions in cells, although typical methods require the interacting groups to be quite close. Here, the authors present a fluorescent technique using singlet oxygen for the imaging of more distant protein–protein interactions.
- Tsz-Leung To
- , Michael J. Fadul
- & Xiaokun Shu
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Centrin3 in trypanosomes maintains the stability of a flagellar inner-arm dynein for cell motility
Beating flagella are essential for the locomotion of Trypanosoma brucei, the causative agent of human sleeping sickness. Here, Wei et al. identify a role for one of five centrin proteins, TbCentrin3, in stabilizing the assembly of a dynein motor essential for flagellar motility.
- Ying Wei
- , Huiqing Hu
- & Ziyin Li
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Article |
Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program
The pioneer factor FOXA1 contributes to androgen receptor (AR)-dependent gene expression by opening chromatin to facilitate AR binding. Here, Jin et al.show that because FOXA1 promotes AR association to many low-affinity sites, excessive FOXA1 can lead to reduced AR availability for specific sites.
- Hong-Jian Jin
- , Jonathan C. Zhao
- & Jindan Yu
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Article |
MitoNEET-mediated effects on browning of white adipose tissue
Mice overexpressing the mitochondrial protein MitoNEET in white adipose tissue (WAT) are very fat but metabolically healthy. Here the authors study the physiological consequences of MitoNEET overexpression in WAT, showing that this triggers an initial browning and that the subsequently expanded WAT is less fibrotic.
- Christine M. Kusminski
- , Jiyoung Park
- & Philipp E. Scherer
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Article |
Structural basis for histone mimicry and hijacking of host proteins by influenza virus protein NS1
The influenza A H3N2 subtype protein NS1 possesses a short sequence resembling the N-terminal tail of histone H3 that is used to hijack host proteins. Here, Qin et al.establish the structural basis for the imperfect NS1 mimicry, which allows the virus to target only a subset of chromatin interactors.
- Su Qin
- , Yanli Liu
- & Jinrong Min
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Article |
Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling
Integrin signalling has been implicated in liver regeneration but the molecular processes are not well understood. Here the authors show that β1-integrin is required for liver regeneration and that its absence impairs ligand-induced activation of the epidermal growth factor receptor in mice.
- Tobias Speicher
- , Beat Siegenthaler
- & Sabine Werner
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Article |
A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins
Formation of infectious dengue virus in host cells requires a rearrangement of viral envelope proteins that is triggered by the acidic environment within secretory vesicles. Here, the authors describe the molecular mechanism underlying such rearrangement.
- Aihua Zheng
- , Fei Yuan
- & Margaret Kielian
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Article
| Open AccessTranscription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain
In response to neuronal injury or disease, microglia adopt distinct reactive phenotypes via the expression of proteins, such as the purinergic P2X4 receptor. Here, Masuda et al.show that the transcription factor axis, interferon regulatory factor-8 and -5, drives the expression of P2X4 receptor in microglia and the adoption of a reactive phenotype after peripheral nerve injury.
- Takahiro Masuda
- , Shosuke Iwamoto
- & Kazuhide Inoue
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Structural basis for oligomerization of auxin transcriptional regulators
The transcriptional effects of auxin signalling are mediated by auxin response factors (ARFs) that interact with inhibitory IAA proteins. Nanao et al.present the crystal structure of domain III/IV of ARF5, revealing the structural basis for its interaction with IAAs and its potential to trigger ARF5 oligomerization.
- Max H. Nanao
- , Thomas Vinos-Poyo
- & Renaud Dumas
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Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance
Superoxide dismutase 1 protects cells from reactive oxygen species by catalysing the conversion of superoxide into hydrogen peroxide. Tsang et al.show that this enzyme also plays a transcriptional role in the nucleus, regulating antioxidant gene expression in response to oxidative stress signalling.
- Chi Kwan Tsang
- , Yuan Liu
- & X. F. S. Zheng
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The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein
The TORC1 complex regulates cell growth and metabolism in response to nutrient availability. Boeckstaens et al.demonstrate that following amino-acid starvation, the TORC1 effector Npr1 stimulates ammonium uptake through the Mep2 transporter by phosphorylating and inactivating an inhibitory domain.
- Mélanie Boeckstaens
- , Elisa Llinares
- & Anna Maria Marini
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Article
| Open AccessActomyosin-dependent formation of the mechanosensitive talin–vinculin complex reinforces actin anchoring
The interaction between focal adhesion proteins vinculin and talin is stimulated by mechanical stretching. Here the authors reconstitute actomyosin-dependent stretching of talin in vitro, and show that the resulting activation of vinculin reinforces anchoring of the adhesion complex to actin.
- Corina Ciobanasu
- , Bruno Faivre
- & Christophe Le Clainche
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Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation
The mitochondrial transcription factor TFAM is a multifunctional DNA-binding protein essential for transcriptional regulation and mitochondrial DNA organization. Here, Ngo et al.present two novel crystal structures that provide additional mechanistic insight into how TFAM performs its diverse functions.
- Huu B. Ngo
- , Geoffrey A. Lovely
- & David C. Chan
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