6533b822fe1ef96bd127d96e
RESEARCH PRODUCT
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
Karsten BoldtJeroen Van ReeuwijkGerard DoughertyIdeke J C LamersKarlien L M CoeneHeleen H ArtsMatthew J BettsTina BeyerEmine BolatChristian Johannes GloecknerKhatera HaidariLisette HetterschijtQianhao LuDaniela IaconisDagan JenkinsFranziska KloseBarbara KnappBrooke LatourStef J F LetteboerCarlo L MarcelisDragana MiticManuela MorleoMachteld M OudKonstantinos KoutroumpasMoniek RiemersmaSusan RixPaulien A TerhalGrischa ToedtTeunis J P Van DamErik De VriezeYasmin WissingerKa Man WuGordana ApicPhilip L BealesThanh-minh T NguyenOliver E BlacqueToby J GibsonMartijn A HuynenNicholas KatsanisHannie KremerHeymut OmranErwin Van WijkUwe WolfrumFrançois KepesErica E DavisYves TexierBrunella FrancoRachel H GilesMarius UeffingRobert B RussellRonald RoepmanUk10k Rare Diseases GroupSaeed Al-turkiCarl AndersonDinu AntonyInês BarrosoSylvia E C Van BeersumJamie BenthamShoumo BhattacharyaKeren CarssKrishna ChatterjeeSebahattin CirakCatherine CosgrovePetr DanecekRichard DurbinDavid FitzpatrickJamie FloydNicola HornA. Reghan FoleyChris FranklinMarta FutemaSteve E HumphriesMatt HurlesChris JoyceShane MccarthyHannah M MitchisonDawn MuddymanFrancesco MuntoniJason R WillerStephen O'rahillyAlexandros OnoufriadisFelicity PayneVincent PlagnolLucy RaymondDavid B SavagePeter ScamblerMiriam SchmidtsNadia SchoenmakersRobert SempleDorus A MansEva SerraJim StalkerMargriet Van KogelenbergParthiban VijayarangakannanKlaudia WalterRos WhittallKathy Williamsonsubject
Proteomics0301 basic medicineSystems AnalysisDNA Mutational Analysislnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]General Physics and AstronomyDatasets as Topicmethods [Chromatography Affinity]ProteomicsSensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]Chromatography AffinityMass SpectrometryProtein Interaction Mappingtherapy [Ciliopathies]genetics [Ciliopathies]methods [Molecular Targeted Therapy]Molecular Targeted TherapyProtein Interaction MapsMultidisciplinaryCiliumChemistry (all)Qabnormalities [Spine]pathology [Ciliopathies]genetics [Muscle Hypotonia]therapy [Muscle Hypotonia]Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]metabolism [Proteins]isolation & purification [Proteins]physiology [Biological Transport]3. Good healthCell biologyVesicular transport proteinpathology [Dwarfism]metabolism [Cilia]Muscle Hypotoniaddc:500pathology [Muscle Hypotonia]pathology [Spine]genetics [Dwarfism]Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]ScienceDwarfismExocystBiologyArticleGeneral Biochemistry Genetics and Molecular BiologyPhysics and Astronomy (all)03 medical and health sciencesIntraflagellar transportCiliogenesisOrganelleHumansCiliaBiochemistry Genetics and Molecular Biology (all)ProteinsBiological TransportGeneral Chemistrytherapy [Dwarfism]Fibroblastsgenetics [Proteins]CiliopathiesSpinemethods [Protein Interaction Mapping]Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]030104 developmental biologyProteostasisHEK293 Cellsmethods [Proteomics]description
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-05-13 |