Journal Article

DZNE-2020-04883

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Boldt, K. ; van Reeuwijk, J. ; Lu, Q. ; Koutroumpas, K. ; Nguyen, T. T. ; Texier, Y. ; van Beersum, S. E. C. ; Horn, N. ; Willer, J. R. ; Mans, D. A. ; Dougherty, G. ; Lamers, I. J. C. ; Coene, K. L. M. ; Arts, H. H. ; Betts, M. J. ; Beyer, T. ; Bolat, E. ; Gloeckner, C. J.DZNE* ; Haidari, K. ; Hetterschijt, L. ; Iaconis, D. ; Jenkins, D. ; Klose, F. ; Knapp, B. ; Latour, B. ; Letteboer, S. J. F. ; Marcelis, C. L. ; Mitic, D. ; Morleo, M. ; Oud, M. M. ; Riemersma, M. ; Rix, S. ; Terhal, P. A. ; Toedt, G. ; van Dam, T. J. P. ; de Vrieze, E. ; Wissinger, Y. ; Wu, K. M. ; Apic, G. ; Beales, P. L. ; Blacque, O. E. ; Gibson, T. J. ; Huynen, M. A. ; Katsanis, N. ; Kremer, H. ; Omran, H. ; van Wijk, E. ; Wolfrum, U. ; Kepes, F. ; Davis, E. E. ; Franco, B. ; Giles, R. H. ; Ueffing, M. (Corresponding author) ; Russell, R. B. ; Roepman, R. ; Group, U. R. D. ; Al-Turki, S. ; Anderson, C. ; Antony, D. ; Barroso, I. ; Bentham, J. ; Bhattacharya, S. ; Carss, K. ; Chatterjee, K. ; Cirak, S. ; Cosgrove, C. ; Danecek, P. ; Durbin, R. ; Fitzpatrick, D. ; Floyd, J. ; Reghan Foley, A. ; Franklin, C. ; Futema, M. ; Humphries, S. E. ; Hurles, M. ; Joyce, C. ; McCarthy, S. ; Mitchison, H. M. ; Muddyman, D. ; Muntoni, F. ; O'Rahilly, S. ; Onoufriadis, A. ; Payne, F. ; Plagnol, V. ; Raymond, L. ; Savage, D. B. ; Scambler, P. ; Schmidts, M. ; Schoenmakers, N. ; Semple, R. ; Serra, E. ; Stalker, J. ; van Kogelenberg, M. ; Vijayarangakannan, P. ; Walter, K. ; Whittall, R. ; Williamson, K.

2016
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/ncomms11491

Abstract: 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.

Keyword(s): Biological Transport: physiology (MeSH) ; Chromatography, Affinity: methods (MeSH) ; Cilia: metabolism (MeSH) ; Ciliopathies: genetics (MeSH) ; Ciliopathies: pathology (MeSH) ; Ciliopathies: therapy (MeSH) ; DNA Mutational Analysis (MeSH) ; Datasets as Topic (MeSH) ; Dwarfism: genetics (MeSH) ; Dwarfism: pathology (MeSH) ; Dwarfism: therapy (MeSH) ; Fibroblasts (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Mass Spectrometry (MeSH) ; Molecular Targeted Therapy: methods (MeSH) ; Muscle Hypotonia: genetics (MeSH) ; Muscle Hypotonia: pathology (MeSH) ; Muscle Hypotonia: therapy (MeSH) ; Protein Interaction Mapping: methods (MeSH) ; Protein Interaction Maps (MeSH) ; Proteins: genetics (MeSH) ; Proteins: isolation & purification (MeSH) ; Proteins: metabolism (MeSH) ; Proteomics: methods (MeSH) ; Spine: abnormalities (MeSH) ; Spine: pathology (MeSH) ; Systems Analysis (MeSH) ; Proteins

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Contributing Institute(s):

1. Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases (AG Gloeckner)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2016

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