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| Open AccessGlobal stable-isotope tracing metabolomics reveals system-wide metabolic alternations in aging Drosophila
Stable-isotope tracing allows quantifying metabolic activity by measuring isotopically labeled metabolites, but its metabolome coverage has been limited. Here, the authors develop a global isotope tracing approach with metabolome-wide coverage and use it to characterize metabolic activities in aging Drosophila.
- Ruohong Wang
- , Yandong Yin
- & Zheng-Jiang Zhu
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Article
| Open AccessA streamlined platform for analyzing tera-scale DDA and DIA mass spectrometry data enables highly sensitive immunopeptidomics
Immunopeptidomics benefits from highly sensitive mass spectrometry (MS). Here, the authors present a computational platform for integrating data-dependent and -independent acquisition MS approaches, and demonstrate its utility for deeper immunopeptidome profiling.
- Lei Xin
- , Rui Qiao
- & Ming Li
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Article
| Open AccessComprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease
Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.
- Gemma Cadby
- , Corey Giles
- & Eric K. Moses
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Article
| Open AccessHistone functions as a cell-surface receptor for AGEs
Advanced glycation end products (AGEs) are believed to be pathogenic molecules that mediate pro-inflammatory responses. Here the authors identify histone as a cell-surface receptor for AGEs and show that AGEs may also be involved in the homeostatic response via binding to histone.
- Masanori Itakura
- , Kosuke Yamaguchi
- & Koji Uchida
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Article
| Open AccessHyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
In this work, the authors report that hyperphosphorylated recombinant tau spontaneously assembles into small, amorphous aggregates, which disrupt membranes and induce Toll-like receptor 4-dependent responses in human macrophages.
- Jonathan X. Meng
- , Yu Zhang
- & David Klenerman
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Article
| Open AccessDual-resolving of positional and geometric isomers of C=C bonds via bifunctional photocycloaddition-photoisomerization reaction system
The simultaneous identification of position and configuration of double bonds in unsaturated lipids is challenging. Here, the authors develop a workflow for deep structural lipidomics to address this issue using a bifunctional reaction system combined with liquid chromatography-mass spectrometry, revealing double bond patterns in bacteria and in mouse brain ischemia.
- Guifang Feng
- , Ming Gao
- & Suming Chen
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Article
| Open AccessNext-generation biomonitoring of the early-life chemical exposome in neonatal and infant development
Exposure to synthetic and natural toxicants is a major risk factor in the etiology of disease. Here, authors describe the development of a method to quantify >80 xenobiotics and apply it to assess early-life exposure in vulnerable infants.
- Thomas Jamnik
- , Mira Flasch
- & Benedikt Warth
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Article
| Open AccessBenchmarking of analysis strategies for data-independent acquisition proteomics using a large-scale dataset comprising inter-patient heterogeneity
Data independent acquisition (DIA) has been gaining momentum in clinical proteomics. Here, the authors create a benchmark dataset comprising inter-patient heterogeneity to compare popular DIA data analysis workflows for identifying differentially abundant proteins.
- Klemens Fröhlich
- , Eva Brombacher
- & Oliver Schilling
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Article
| Open AccessWater coordinated on Cu(I)-based catalysts is the oxygen source in CO2 reduction to CO
Understanding the underlying mechanisms for catalytic reduction of CO2 over Cu based catalysts remains challenging. Here, the authors develop an effective method to reveal the vital roles of H2O in promoting metal catalysts to CO2 reduction via a modified triple stage quadrupole mass spectrometer.
- Yajun Zheng
- , Hedan Yao
- & Zhiping Zhang
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Article
| Open AccessPytheas: a software package for the automated analysis of RNA sequences and modifications via tandem mass spectrometry
RNA modifications represent a critical aspect of RNA biology that is not well suited to sequencing methods. Here, the authors provide a software tool for automated analysis of RNA tandem mass spectra with full support of modifications, isotope labelling, and control of false discovery rate.
- Luigi D’Ascenzo
- , Anna M. Popova
- & James R. Williamson
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Article
| Open AccessThree-dimensional structure determination of protein complexes using matrix-landing mass spectrometry
Mass spectrometry (MS) is a powerful tool for the structural characterization of protein complexes. Here the authors offer a path for direct integration of MS and electron microscopy with a MS approach that enables grid deposition and structural preservation of gaseous protein complex ions.
- Michael S. Westphall
- , Kenneth W. Lee
- & Joshua J. Coon
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Article
| Open AccessPeptidoglycan biosynthesis is driven by lipid transfer along enzyme-substrate affinity gradients
Bacterial cell wall enzymes and their precursors are critical targets for antibiotic development. Here, the authors investigate several biosynthetic enzymes with their substrates and show that the passage of substrates and products in the pathway is controlled by their relative binding affinities.
- Abraham O. Oluwole
- , Robin A. Corey
- & Carol V. Robinson
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Article
| Open AccessHidden information on protein function in censuses of proteome foldedness
Proteomics can define features of proteome foldedness by assessing the reactivity of surface exposed amino acids. Here, the authors show that such exposure patterns yield insight to structural changes in chaperones as they bind to unfolded proteins in urea-denatured mammalian cell lysate.
- Dezerae Cox
- , Ching-Seng Ang
- & Danny M. Hatters
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Article
| Open AccessAuxiliary ATP binding sites support DNA unwinding by RecBCD
RecBCD is a remarkably fast DNA helicase. Using a battery of biophysical methods, Zananiri et. al reveal additional, non-catalytic ATP binding sites that increase the ATP flux to the catalytic sites that allows fast unwinding when ATP is scarce.
- Rani Zananiri
- , Sivasubramanyan Mangapuram Venkata
- & Arnon Henn
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Article
| Open AccessCharacterization of protein unfolding by fast cross-linking mass spectrometry using di-ortho-phthalaldehyde cross-linkers
Conformations sampled by a protein while it unfolds are difficult to visualize. Here, the authors develop di-ortho-phthalaldehyde cross-linkers for rapid chemical cross-linking mass spectrometry analysis and demonstrate that this method captures the conformations of protein unfolding intermediates.
- Jian-Hua Wang
- , Yu-Liang Tang
- & Xiaoguang Lei
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Article
| Open AccessBacterial F-type ATP synthases follow a well-choreographed assembly pathway
ATPases are the macromolecular machines for cellular energy production. Here the authors investigate factors that govern the assembly of the F1 complex from a bacterial F-type ATPase and relate differences in activity of complexes assembled in cells and in vitro to structural changes.
- Khanh Vu Huu
- , Rene Zangl
- & Nina Morgner
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Article
| Open AccessAn efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease
Gluten peptides from wheat enter the bloodstream and are excreted in urine but are yet to be chemically characterised. Here, the authors show by mass spectrometry that quantitative and qualitative differences in urinary peptides can be detected between healthy people and patients with celiac disease.
- Brad A. Palanski
- , Nielson Weng
- & Joshua E. Elias
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Article
| Open AccessComparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans
Untargeted mass spectrometry-based metabolomics can reveal new biochemistry, but data analysis is challenging. Here, the authors develop Metaboseek, an open-source software that facilitates metabolite discovery, and apply it to characterize fatty acid alpha-oxidation in C. elegans.
- Maximilian J. Helf
- , Bennett W. Fox
- & Frank C. Schroeder
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Article
| Open AccessExperimental identification of aminomethanol (NH2CH2OH)—the key intermediate in the Strecker Synthesis
The Strecker synthesis is considered a viable route to amino acids formation on the primordial Earth. Here the authors succeed in observing its elusive intermediate aminomethanol, formed by insertion of an electronically excited oxygen atom in methylamine and stabilized by an icy matrix, using isomer-selective photoionization time-of-flight mass spectrometry during thermal desorption of the ice mixture.
- Santosh K. Singh
- , Cheng Zhu
- & Ralf I. Kaiser
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Article
| Open AccessStreamlined single-cell proteomics by an integrated microfluidic chip and data-independent acquisition mass spectrometry
Single-cell proteomics is an emerging approach to characterize cell-to-cell differences. Here, the authors develop chips that enable complete proteomic sample processing down to the single-cell level and integrate them with DIA-MS into a streamlined single-cell proteomics workflow.
- Sofani Tafesse Gebreyesus
- , Asad Ali Siyal
- & Hsiung-Lin Tu
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Article
| Open AccessLipidomic profiling of human serum enables detection of pancreatic cancer
Patients with pancreatic cancer have a poor prognosis, more research is required to identify the disease at an earlier stage. Here, the authors use lipid profiles of blood samples and show that they can distinguish patients with pancreatic cancer from healthy controls.
- Denise Wolrab
- , Robert Jirásko
- & Michal Holčapek
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Article
| Open AccessA mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their disease-associated regulation
Different phosphoinositide isomers are involved in a variety of physiological and pathological processes. Here, the authors combine chiral column chromatography and mass spectrometry to measure phosphoinositide regioisomers, revealing their dynamic changes in intra- and extracellular cancer cell milieus.
- Shin Morioka
- , Hiroki Nakanishi
- & Takehiko Sasaki
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Article
| Open AccessLinking post-translational modifications and protein turnover by site-resolved protein turnover profiling
Post-translational modifications (PTMs) can regulate cellular protein function but their global impact on protein turnover is largely unknown. Here, the authors develop proteomic workflows to profile PTM-resolved protein turnover and analyze the effects of phosphorylation, acetylation and ubiquitination.
- Jana Zecha
- , Wassim Gabriel
- & Bernhard Kuster
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Article
| Open AccessCritical Assessment of MetaProteome Investigation (CAMPI): a multi-laboratory comparison of established workflows
The authors present CAMPI, a large-scale multi-lab comparison of diverse metaproteomics workflows. CAMPI provides insights into the robustness of current methods, suggests further improvements to the field, and may pave the way for future community-driven metaproteomics projects.
- Tim Van Den Bossche
- , Benoit J. Kunath
- & Thilo Muth
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Article
| Open AccessNanoparticles and photochemistry for native-like transmembrane protein footprinting
The intrinsic flexibility of membranes proteins still poses a challenge in determining their active structure. Here the authors describe the development of a method that combines chemical footprinting and mass spectrometry to assist in determining the structure of native membrane proteins and their dynamics.
- Jie Sun
- , Xiaoran Roger Liu
- & Michael L. Gross
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Article
| Open AccessSynthesis and structure elucidation of the human tRNA nucleoside mannosyl-queuosine
Mannosyl-queuosine (manQ) is a non-canonical RNA nucleoside present in the anticodon loop of certain tRNAs. Here, the authors use a combination of total synthesis and mass spectrometry to contradict the literature-reported structure and show that manQ features an alpha-allyl connectivity of its mannose moiety.
- Markus Hillmeier
- , Mirko Wagner
- & Thomas Carell
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Article
| Open AccessSpatial-proteomics reveals phospho-signaling dynamics at subcellular resolution
Protein activity regulated by phosphorylation can result in subcellular relocation. Here, the authors present a high throughput spatial phosphoproteomics approach to profile six subcellular compartments, providing insights into EGFR and stress signalling dynamics.
- Ana Martinez-Val
- , Dorte B. Bekker-Jensen
- & Jesper V. Olsen
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Article
| Open AccessAn atlas of protein turnover rates in mouse tissues
Protein turnover underpins biology but is challenging to measure in vivo across the entire proteome. Here, the authors provide a comprehensive resource of protein turnover in mouse tissues and develop a visualization platform to analyze these data.
- Zach Rolfs
- , Brian L. Frey
- & Nathan V. Welham
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Article
| Open AccessMapping enzyme catalysis with metabolic biosensing
The testing of engineered enzymes represents a bottleneck. Here the authors report a screening method combining microfluidics and mass spectrometry, to map the catalysis of a mutated enzyme, characterise the range of products generated and recover the sequences of variants with desired activities.
- Linfeng Xu
- , Kai-Chun Chang
- & Adam R. Abate
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Article
| Open AccessA novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems
Lipid nanoparticle delivery of mRNA vaccines has become of particular importance, however, mRNA stability is a major concern. Here, the authors report on a study of lipid impurity mRNA interactions using reverse phase ion pair HPLC to identify reactions which render the mRNA untranslatable, reducing vaccine efficiency.
- Meredith Packer
- , Dipendra Gyawali
- & Phil White
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Article
| Open AccessIdentification of proximal SUMO-dependent interactors using SUMO-ID
Several proteomic approaches allow the analysis of covalent protein SUMOylation, but it remains challenging to systematically study the consequences of a substrate being modified. Here, the authors combine proximity biotinylation and protein-fragment complementation to identify SUMO-dependent protein interactors.
- Orhi Barroso-Gomila
- , Fredrik Trulsson
- & James D. Sutherland
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Article
| Open Access2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases
The human 2-oxoglutarate (2OG) oxygenases FIH and AspH are relevant drug targets. Here, the authors show that synthetic and naturally occurring 2OG derivatives can selectively modulate FIH and AspH activities, suggesting that these compounds may serve as a basis to develop 2OG oxygenase-targeting probes and drugs.
- Yu Nakashima
- , Lennart Brewitz
- & Christopher J. Schofield
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Article
| Open AccessStructural library and visualization of endogenously oxidized phosphatidylcholines using mass spectrometry-based techniques
Oxidized phosphatidylcholines (oxPCs) are a structurally diverse class of lipids associated with various diseases. Here, the authors use mass spectrometry to construct a spectral library of 465 oxPCs and subsequently profile oxPCs formed during acetaminophen-induced acute liver failure in mice.
- Yuta Matsuoka
- , Masatomo Takahashi
- & Ken-ichi Yamada
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Article
| Open AccessNuclear S-nitrosylation impacts tissue regeneration in zebrafish
The role of the post-translational modifications in tissue regeneration is still not clearly understood. Here, the authors show that many nuclear proteins change S-nitrosylation state in the regenerating zebrafish tailfin, highlighting the importance of Kdm1a S-nitrosylation in the repair process.
- Gianfranco Matrone
- , Sung Yun Jung
- & John P. Cooke
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Article
| Open AccessHigh-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip
Single-cell proteomics is an emerging technology but protein coverage, throughput and quantitation accuracy are often still insufficient. Here, the authors develop a nested nanowell chip that improves protein recovery, throughput and robustness of isobaric labeling-based quantitative single-cell proteomics.
- Jongmin Woo
- , Sarah M. Williams
- & Ying Zhu
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Article
| Open AccessStructural basis of soluble membrane attack complex packaging for clearance
To prevent unregulated complement activation, extracellular chaperones capture soluble precursors to the membrane attack complex (sMAC). Here, structural analysis of sMAC reveals how clusterin recognizes heterogeneous sMAC complexes and inhibits polymerization of complement protein C9.
- Anaïs Menny
- , Marie V. Lukassen
- & Doryen Bubeck
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Article
| Open AccessGproDIA enables data-independent acquisition glycoproteomics with comprehensive statistical control
Data independent acquisition (DIA) proteomics provides deep coverage and high quantitative accuracy, but is not yet well established in glycoproteomics. Here, the authors develop a DIA-based glycoproteomics workflow with stringent statistical controls to enable accurate glycopeptide identification.
- Yi Yang
- , Guoquan Yan
- & Liang Qiao
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Article
| Open AccessThe regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome
ADP-ribosylation is regulated by HPF1 and ARH3, but the cellular target spectrum of these enzymes is not fully understood. Here, the authors use quantitative proteomics to define the HPF1- and ARH3-dependent ADP-ribosylome, providing evidence that mono-ADP-ribosylation of serine predominates in cells.
- Ivo A. Hendriks
- , Sara C. Buch-Larsen
- & Michael L. Nielsen
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Article
| Open AccessA scalable workflow to characterize the human exposome
Humans are exposed to millions of chemicals but mass spectrometry (MS)-based targeted biomonitoring assays are usually limited to a few hundred known hazards. Here, the authors develop a workflow for MS-based untargeted exposome profiling of known and unidentified environmental chemicals.
- Xin Hu
- , Douglas I. Walker
- & Dean P. Jones
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Article
| Open AccessTime-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale
Combining improved sample preparation, data-independent acquisition mass spectrometry and deep learning, the authors develop a workflow for more robust and precise quantitative ubiquitinome profiling. They use this method to characterize targets of the deubiquitinase USP7 and effects of USP7 inhibitors.
- Martin Steger
- , Vadim Demichev
- & Henrik Daub
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Article
| Open AccessSequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation
The Spike protein of SARS-CoV-2 has a C-terminal cytoplasmic tail. Here the authors show that this tail binds trafficking machinery via sequences that appear optimised to ensure that Spike accumulates at the site of viral budding in the Golgi but that some can also traffic to the cell surface to induce syncytia formation.
- Jérôme Cattin-Ortolá
- , Lawrence G. Welch
- & Sean Munro
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Article
| Open AccessOff-the-shelf proximity biotinylation for interaction proteomics
Proximity biotinylation is a powerful tool to profile interactomes, but it requires genetic engineering of the target protein. Here, the authors develop a proximity biotinylation enzyme that can be directed to the target using antibodies, enabling interactome profiling of endogenous proteins or PTMs.
- Irene Santos-Barriopedro
- , Guido van Mierlo
- & Michiel Vermeulen
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Article
| Open AccessA hierarchical approach to removal of unwanted variation for large-scale metabolomics data
Mass spectrometry-based metabolomics is a powerful method for profiling large clinical cohorts but batch variations can obscure biologically meaningful differences. Here, the authors develop a computational workflow that removes unwanted data variation while preserving biologically relevant information.
- Taiyun Kim
- , Owen Tang
- & Jean Yee Hwa Yang
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Article
| Open AccessThe conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core
The pro-apoptotic BAX protein is a monomer under homeostatic conditions and, in response to stress, transforms into oligomers that induce apoptosis. Here, the authors characterize structural features of BAX that individually stabilize the monomer while collectively contributing to oligomerization.
- Noah B. Bloch
- , Thomas E. Wales
- & Loren D. Walensky
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Article
| Open AccessSpontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters
Analogues of α-ketoglutarate are used in many cellular studies but assumptions are made about cellular uptake. Here, the authors show that esterified analogues rapidly hydrolyse in aqueous medium resulting in an analogue which can be quickly taken up by many cell lines, contrary to prevailing assumptions.
- Seth J. Parker
- , Joel Encarnación-Rosado
- & Alec C. Kimmelman
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Article
| Open AccessIceR improves proteome coverage and data completeness in global and single-cell proteomics
Label-free quantitative proteomics by data dependent acquisition offers high protein identification rates but is often limited by missing values. Here, the authors develop a quantification workflow that substantially reduces missing values while maintaining high identification rates and quantification accuracy.
- Mathias Kalxdorf
- , Torsten Müller
- & Jeroen Krijgsveld
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Matters Arising
| Open AccessQuality control requirements for the correct annotation of lipidomics data
- Harald C. Köfeler
- , Thomas O. Eichmann
- & Kim Ekroos
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Matters Arising
| Open AccessReply to “Quality control requirements for the correct annotation of lipidomics data”
- Catherine G. Vasilopoulou
- , Karolina Sulek
- & Florian Meier
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Article
| Open AccessThe middle lipin domain adopts a membrane-binding dimeric protein fold
Lipins need to bind cell membranes before they can function as phosphatidic acid phosphatases. Here, the authors elucidate the structural basis of lipin membrane-association and identify a lipin domain with a novel protein fold that is critical for membrane binding and full functionality of lipins.
- Weijing Gu
- , Shujuan Gao
- & Michael V. Airola