An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Karsten Boldt, Jeroen van Reeuwijk, Qianhao Lu, Konstantinos Koutroumpas, Thanh-Minh T. Nguyen, Yves Texier, Sylvia E. C. van Beersum, Nicola Horn, Jason R. Willer, Dorus A. Mans, Gerard Dougherty, Ideke J. C. Lamers, Karlien L. M. Coene, Heleen H. Arts, Matthew J. Betts, Tina Beyer, Emine Bolat, Christian Johannes Gloeckner, Khatera Haidari, Lisette Hetterschijt, Daniela Iaconis, Dagan Jenkins, Franziska Klose, Barbara Knapp, Brooke Latour, Stef J. F. Letteboer, Carlo L. Marcelis, Dragana Mitic, Manuela Morleo, Machteld M. Oud, Moniek Riemersma, Susan Rix, Paulien A. Terhal, Grischa Toedt, Teunis J. P. van Dam, Erik de Vrieze, Yasmin Wissinger, Ka Man Wu, Gordana Apic, Philip L. Beales, Oliver E. Blacque, Toby J. Gibson, Martijn A. Huynen, Nicholas Katsanis, Hannie Kremer, Heymut Omran, Erwin van Wijk, Uwe Wolfrum, François Kepes, Erica E. Davis, Brunella Franco, Rachel H. Giles, Marius Ueffing (), Robert B. Russell () and Ronald Roepman ()
Additional contact information
Karsten Boldt: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Jeroen van Reeuwijk: Radboud University Medical Center
Qianhao Lu: Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
Konstantinos Koutroumpas: Institute of Systems and Synthetic Biology, Genopole, CNRS, Université d’Evry
Thanh-Minh T. Nguyen: Radboud University Medical Center
Yves Texier: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Sylvia E. C. van Beersum: Radboud University Medical Center
Nicola Horn: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Jason R. Willer: Center for Human Disease Modeling, Duke University
Dorus A. Mans: Radboud University Medical Center
Gerard Dougherty: University Children's Hospital Muenster
Ideke J. C. Lamers: Radboud University Medical Center
Karlien L. M. Coene: Radboud University Medical Center
Heleen H. Arts: Radboud University Medical Center
Matthew J. Betts: Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
Tina Beyer: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Emine Bolat: Radboud University Medical Center
Christian Johannes Gloeckner: German Center for Neurodegenerative Diseases (DZNE) within the Helmholz Association
Khatera Haidari: Regenerative Medicine Center, University Medical Center Utrecht
Lisette Hetterschijt: Cognition and Behaviour, Radboud University Medical Center
Daniela Iaconis: Telethon Institute of Genetics and Medicine
Dagan Jenkins: Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health
Franziska Klose: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Barbara Knapp: Cell and Matrix Biology, Inst. of Zoology, Johannes Gutenberg University of Mainz
Brooke Latour: Radboud University Medical Center
Stef J. F. Letteboer: Radboud University Medical Center
Carlo L. Marcelis: Radboud University Medical Center
Dragana Mitic: Cambridge Cell Networks Ltd
Manuela Morleo: Telethon Institute of Genetics and Medicine
Machteld M. Oud: Radboud University Medical Center
Moniek Riemersma: Radboud University Medical Center
Susan Rix: Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health
Paulien A. Terhal: University Medical Center Utrecht
Grischa Toedt: Structural and Computational Biology Unit, European Molecular Biology Laboratory
Teunis J. P. van Dam: Centre for Molecular and Biomolecular Informatics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Erik de Vrieze: Cognition and Behaviour, Radboud University Medical Center
Yasmin Wissinger: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Ka Man Wu: Radboud University Medical Center
Gordana Apic: Cambridge Cell Networks Ltd
Philip L. Beales: Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health
Oliver E. Blacque: School of Biomolecular & Biomed Science, Conway Institute, University College Dublin
Toby J. Gibson: Structural and Computational Biology Unit, European Molecular Biology Laboratory
Martijn A. Huynen: Centre for Molecular and Biomolecular Informatics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Nicholas Katsanis: Center for Human Disease Modeling, Duke University
Hannie Kremer: Cognition and Behaviour, Radboud University Medical Center
Heymut Omran: University Children's Hospital Muenster
Erwin van Wijk: Cognition and Behaviour, Radboud University Medical Center
Uwe Wolfrum: Cell and Matrix Biology, Inst. of Zoology, Johannes Gutenberg University of Mainz
François Kepes: Institute of Systems and Synthetic Biology, Genopole, CNRS, Université d’Evry
Erica E. Davis: Center for Human Disease Modeling, Duke University
Brunella Franco: Telethon Institute of Genetics and Medicine
Rachel H. Giles: Regenerative Medicine Center, University Medical Center Utrecht
Marius Ueffing: Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
Robert B. Russell: Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
Ronald Roepman: Radboud University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11491

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