Featured
-
-
Article
| Open AccessCdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila
Mitochondrial fission, performed by Drp1, is carefully regulated, particularly in neurons. Here, the authors examine Drosophila Cdk8/CDK19 function in mitochondrial fission and uncover a role phosphorylating Drp1 in the cytoplasm and show overexpression suppresses a Parkinson’s disease model.
- Jenny Zhe Liao
- , Hyung-lok Chung
- & Esther M. Verheyen
-
Article
| Open AccessKdpD is a tandem serine histidine kinase that controls K+ pump KdpFABC transcriptionally and post-translationally
KdpD is known as the sensory histidine kinase of two-component system KdpDE that controls the transcription of the kdpFABC genes. Here, the authors show that KdpD acts as atypical serine kinase, which post-translationally regulates KdpFABC.
- Jakob M. Silberberg
- , Sophie Ketter
- & Inga Hänelt
-
Article
| Open AccessNardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.
- Jie Fu
- , Jianhua Ling
- & Paul J. Chiao
-
Article
| Open AccessDbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
-
Article
| Open AccessArchitecture and activation of human muscle phosphorylase kinase
High-resolution cryo-EM study of human muscle phosphorylase kinase reveals its complex structure and how calcium ions activate it, offering insights into glycogen metabolism and kinase regulation.
- Xiaoke Yang
- , Mingqi Zhu
- & Junyu Xiao
-
Article
| Open AccessHigh-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design
Discovery of new therapeutics has been hampered by the often-limiting resolution and throughput of cryo-EM. Here, the authors determine high-resolution cryo-EM structures of the CDK-activating kinase to establish a methodological framework for the use of cryo-EM in structure-based drug design.
- Victoria I. Cushing
- , Adrian F. Koh
- & Basil J. Greber
-
Article
| Open AccessCentrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Jung-Eun Park
- , Tae-Sung Kim
- & Kyung S. Lee
-
Article
| Open AccessSubstrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity
InsP3 3-kinase phosphorylates 1,4,5-trisphosphate (InsP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Here, the authors used a combination of methods to survey InsP3 3-kinase ligand specificity and determined that IP3K specificity surpasses that of its natural substrate, allowing it to bind diverse ligands with a primary hydroxyl in the reactive position and based on a carbohydrate moiety.
- María Ángeles Márquez-Moñino
- , Raquel Ortega-García
- & Beatriz González
-
Article
| Open AccessDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.
- Joel A. Sexton
- , Tony Potchernikov
- & Benjamin E. Turk
-
Article
| Open AccessMolecular basis of VEGFR1 autoinhibition at the plasma membrane
Spontaneous activation of VEGFRs is a hallmark of diabetes and several cancers. Here, the authors show how in VEGFR1 a juxtamembrane segment connecting the catalytic and ligand-binding domains of the receptor can prevent its spontaneous activation.
- Manas Pratim Chakraborty
- , Diptatanu Das
- & Rahul Das
-
Article
| Open AccessDeletion of Aurora kinase A prevents the development of polycystic kidney disease in mice
Using different mouse models of Polycystic Kidney Disease, this research demonstrated that deletion of the Aurora Kinase A gene was able to prevent cyst initiation and growth, identifying it as a central regulator of pathogenesis in this condition.
- Ming Shen Tham
- , Denny L. Cottle
- & Ian M. Smyth
-
Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
-
Article
| Open AccessAutoregulation of the LIM kinases by their PDZ domain
LIM domain kinases are key regulators of cofilin and consequently actin severing. Here, the authors show that the LIMK PDZ domain is important for autoregulation using a conserved surface distal to the canonical PDZ-binding cleft.
- Gabriela Casanova-Sepúlveda
- , Joel A. Sexton
- & Titus J. Boggon
-
Article
| Open AccessStructural basis of a redox-dependent conformational switch that regulates the stress kinase p38α
p38α is a kinase that regulates many cellular processes. Here authors report that redox fluctuations induce conformational changes to fine-tune the p38α activity beyond its activation loop phosphorylation.
- Joan Pous
- , Blazej Baginski
- & Maria J. Macias
-
Article
| Open AccessBiosynthesis of barley wax β-diketones: a type-III polyketide synthase condensing two fatty acyl units
Barley plants coat their organs with waxy diketones to protect against late-summer droughts. These diketones are formed by two enzymes, one diverting common fatty acids from normal metabolism and the other one linking two fatty acid units together.
- Yulin Sun
- , Alberto Ruiz Orduna
- & Reinhard Jetter
-
Article
| Open AccessAn allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function
Protein kinase transition between different conformational states is controlled by autophosphorylation. Here, the authors demonstrate that the c-terminal Tyr530 is a de facto c-Src autophosphorylation site and identify a critical c-terminal palindromic phospho-motif that controls the interplay between substrate and enzyme-acting kinases during autophosphorylation.
- Hipólito Nicolás Cuesta-Hernández
- , Julia Contreras
- & Iván Plaza-Menacho
-
Article
| Open AccessActivation of the integrated stress response by inhibitors of its kinases
The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.
- Maria Szaruga
- , Dino A. Janssen
- & Anne Bertolotti
-
Article
| Open Accessp21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1
PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPARα transrepression and ketone body reduction.
- Min Yan Shi
- , Hwang Chan Yu
- & Eun Ju Bae
-
Article
| Open AccessStructure and regulation of full-length human leucine-rich repeat kinase 1
Leucine-rich repeat kinase 1 (LRRK1) and its counterpart LRRK2 play crucial roles in regulating fundamental cellular processes. Here, the authors use cryo-EM to characterize the LRRK1 monomer and dimer, revealing interfaces that regulate kinase activity and structural differences to LRRK2.
- Riley D. Metcalfe
- , Juliana A. Martinez Fiesco
- & Ping Zhang
-
Article
| Open AccessSmall molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels
Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.
- Rachel J. Roth Flach
- , Eliza Bollinger
- & Kevin J. Filipski
-
Article
| Open AccessCryo-EM structure of a RAS/RAF recruitment complex
RAF kinases are autoinhibited in the cytosol and are activated by recruitment to the plasma membrane by GTP-bound RAS. Here, the authors describe cryoEM structures of a membrane-free KRAS/BRAF/MEK/14-3-3 complex that capture a pre-activation intermediate with BRAF still in an autoinhibited state.
- Eunyoung Park
- , Shaun Rawson
- & Michael J. Eck
-
Article
| Open AccessModulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging
The extent of phosphorylated p38 MAPK is known to determine signaling. Here, the authors show the relative pool of non-phosphorylated p38 MAPK modulates signaling output to control growth, lysosome formation and neuronal integrity during early aging.
- Wang Yuan
- , Yi M. Weaver
- & Benjamin P. Weaver
-
Article
| Open AccessSequestration of histidine kinases by non-cognate response regulators establishes a threshold level of stimulation for bacterial two-component signaling
Bacterial two-component systems consist of a sensor histidine kinase (HK) that perceives a signal, and a cognate response regulator (RR) that modulates target gene expression. Here, the authors combine experiments and mathematical modelling to show that phosphorylated HKs can be sequestered by non-cognate RRs, which prevents responses to weak signals.
- Gaurav D. Sankhe
- , Rubesh Raja
- & Deepak Kumar Saini
-
Article
| Open AccessRAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa
ERK signalling is a core developmental pathway that is canonically activated by RTKs through activated RAS. Here they show that the process of ERK activation in skeletogenic precursors of the sea urchin embryo is growth factor and RAS-independent, uncovering a new mode of ERK signalling in non-chordate metazoa.
- Aline Chessel
- , Noémie De Crozé
- & Thierry Lepage
-
Article
| Open AccessAn optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells
Different activation patterns of Akt kinase direct downstream signaling outcomes. Here, the authors run phosphoproteomics on optogenetically-activated Akt1 to characterize the phosphorylation circuits induced by different intensities, durations, and patterns of stimulation.
- Wenping Zhou
- , Wenxue Li
- & Yansheng Liu
-
Article
| Open AccessStructural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
PEAK pseudokinases are emerging disease targets, which regulate cell migration and proliferation through protein scaffolding. Here, the authors present the cryo-EM structure of the PEAK3/14-3-3 complex and reveal how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
- Hayarpi Torosyan
- , Michael D. Paul
- & Kliment A. Verba
-
Article
| Open AccessStructural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling
The PEAK family of pseudokinases are key hubs in cellular signalling, including cell motility and cancer. Here, the authors characterise how PEAK proteins interact with the adapter proteins CrkII and Grb2 and regulatory scaffold protein 14-3-3, to achieve functional signalling assemblies.
- Michael J. Roy
- , Minglyanna G. Surudoi
- & Isabelle S. Lucet
-
Article
| Open AccessCharacterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway
The p38α protein kinase is an attractive druggable target for many human diseases. Here, the authors show how the structural plasticity of p38α can be leveraged to selectively inhibit a subset of the functions regulated by this kinase and aid in the development of therapeutic compounds.
- Lorena González
- , Lucía Díaz
- & Angel R. Nebreda
-
Article
| Open AccessDevelopment of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding
Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.
- Erik B. Faber
- , Luxin Sun
- & Gunda I. Georg
-
Article
| Open AccessAn Aurora B-RPA signaling axis secures chromosome segregation fidelity
RPA is a master coordinator of DNA metabolism. Here, authors uncover that RPA is regulated by an Aurora B-signaling circuit that is critical for chromosome segregation in mitosis. Distinct phosphorylation of RPA70 modulates accessibility of RPA domains.
- Poonam Roshan
- , Sahiti Kuppa
- & Sofia Origanti
-
Article
| Open AccessAMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration
Cell metabolism must adapt to the energy needs of migrating cells. This study finds that fast amoeboid migrating cells harbor high AMPK activity, which controls both mitochondrial dynamics and cytoskeletal remodeling, enabling reduced energy needs.
- Eva Crosas-Molist
- , Vittoria Graziani
- & Victoria Sanz-Moreno
-
Article
| Open AccessCirculating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma
Inhibition of ALK is initially effective in patients with ALK-driven lung cancer but resistance often arises. Here, the authors use circulating tumour DNA, collected as part of a phase I trial investigating lorlatinib (ALK inhibitor) in pediatric patients with ALK-driven neuroblastoma, to detect early resistance mechanisms.
- Esther R. Berko
- , Gabriela M. Witek
- & Yaël P. Mossé
-
Article
| Open AccessDynamic changes of the Prf/Pto tomato resistance complex following effector recognition
Both plant and animals utilize resistant proteins to recognise pathogens. In this work the authors illustrate how bacterial perception by a tomato resistant protein is communicated in order to protect plants against pathogens.
- Arsheed H. Sheikh
- , Iosif Zacharia
- & Vardis Ntoukakis
-
Article
| Open AccessHsp90 provides a platform for kinase dephosphorylation by PP5
PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5.
- Maru Jaime-Garza
- , Carlos A. Nowotny
- & David A. Agard
-
Article
| Open AccessStructural mechanism of a drug-binding process involving a large conformational change of the protein target
Atomic-level descriptions of protein–small molecule binding processes that involve a large conformational change of the protein have been elusive. Here, the authors report unguided molecular dynamics simulations of such a process—Abl kinase binding the cancer drug imatinib.
- Pelin Ayaz
- , Agatha Lyczek
- & David E. Shaw
-
Article
| Open AccessStructural features discriminating hybrid histidine kinase Rec domains from response regulator homologs
Bacterial multi-step phospho-relays employ receiver domains that act as intermediaries in phosphoryl shuttling. Here, the authors show that such a domain does not experience structural changes upon pseudo-phosphorylation, in contrast to the well-studied homologs in response regulators.
- Mitchell Brüderlin
- , Raphael Böhm
- & Badri N. Dubey
-
Article
| Open AccessPhosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1
Many kinases phosphorylate proteins on multiple sites, however in most cases it is not known which sites are functionally important. Here, the authors describe a high-throughput approach to quantitatively evaluate the contribution of each phosphosite within a multisite phosphorylated domain.
- Michelle M. Conti
- , Rui Li
- & Jennifer A. Benanti
-
Article
| Open AccessOncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus
The PIK3CA gene is one of the most frequently mutated genes in all of human cancer. Here authors describe the molecular mechanisms underlying how different oncogenic mutations in PIK3CA mediate increased activity.
- Meredith L. Jenkins
- , Harish Ranga-Prasad
- & John E. Burke
-
Article
| Open AccessStructural mechanism of signal transduction in a phytochrome histidine kinase
In this study, authors have solved cryo-EM structures of a bacteriophytochrome in its dark-adapted and illuminated states. The structures reveal the structural mechanism for photoactivation of the phytochrome.
- Weixiao Yuan Wahlgren
- , Elin Claesson
- & Sebastian Westenhoff
-
Article
| Open AccessIntracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation
The carbohydrate binding protein galectin-3 has been linked to diabetes and cancer. Here, authors show that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.
- Xing Chen
- , Chunyu Yu
- & Yongfeng Shang
-
Article
| Open AccessEnhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model
Mutations that enhance the activity of protein kinase C alpha (PKCα) are associated with Alzheimer’s Disease. Here, the authors report that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model.
- Gema Lordén
- , Jacob M. Wozniak
- & Alexandra C. Newton
-
Article
| Open AccessGenerative deep learning enables the discovery of a potent and selective RIPK1 inhibitor
Retrieval of a new starting active compound with a novel scaffold during early drug development is an important but challenging task. Here, the authors propose a generative deep learning model and by applying this model they discover a potent and highly selective RIPK1 inhibitor with a previously unreported scaffold.
- Yueshan Li
- , Liting Zhang
- & Shengyong Yang
-
Article
| Open AccessBiochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
Although small molecule tyrosine kinase inhibitors are effective in lung cancer driven by mutated EGFR, some receptor variants fail to respond. Here, the authors identify structural features of an important set of EGFR variants with reduced inhibitor sensitivity, guiding future inhibitor selection.
- Iris K. van Alderwerelt van Rosenburgh
- , David M. Lu
- & Yuko Tsutsui
-
Article
| Open AccessFunctional selectivity of insulin receptor revealed by aptamer-trapped receptor structures
DNA aptamers can activate insulin receptor as selective agonists or positive allosteric modulators. Here, authors determine structures of the insulin receptor bound to aptamers and provide a basis for the selective activation or allosteric regulation of insulin receptor.
- Junhong Kim
- , Na-Oh Yunn
- & Yunje Cho
-
Article
| Open AccessChemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors
Virtual screening of huge libraries is successful in identifying drug leads. Here, the authors describe a computational strategy, Chemical Space Docking, which combines docking with a reaction-based search of compounds, thereby enabling the exploration of billions of compounds and beyond.
- Paul Beroza
- , James J. Crawford
- & Christian Lemmen
-
Article
| Open AccessAn intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment
Phosphorylation at multiple sites is a major regulatory mechanism in cellular signalling. Here, the authors show that multisite phosphorylation of the c-JUN transcription factor by the JNK kinase exhibits intrinsic kinetics that allow a precise and timed regulation of the transcriptional output.
- Christopher A. Waudby
- , Saul Alvarez-Teijeiro
- & Anastasia Mylona
-
Article
| Open AccessActivation of the human insulin receptor by non-insulin-related peptides
The regulation of plasma glucose levels is effected by insulin. Here, the authors reveal atomic detail of how peptides distinct from insulin bind to and activate the insulin receptor, with implications for design of small-molecule insulin mimetics.
- Nicholas S. Kirk
- , Qi Chen
- & Michael C. Lawrence
-
Article
| Open AccessReaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells
Fluorogenic detection of H2O2 in cells is established, but equivalent tools to monitor its cellular targets remain in their infancy. Here authors develop fluorogenic probes for detecting cysteine sulfenic acid, a redox modification inextricably linked to H2O2 signalling and oxidative stress.
- Renan B. Ferreira
- , Ling Fu
- & Kate S. Carroll
-
Article
| Open AccessKSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data
Kinases are important drug targets, but predicting their activities from phosphoproteomics data remains challenging. While many existing prediction tools rely on phosphosite-specific quantitative data, Crowl et al. develop a kinase activity prediction algorithm that requires no phosphosite quantification.
- Sam Crowl
- , Ben T. Jordan
- & Kristen M. Naegle