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Nat Commun. 2016 May 13;7:11491. doi: 10.1038/ncomms11491.

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

Author information

1
Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, 72074 Tuebingen, Germany.
2
Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
3
Biochemie Zentrum Heidelberg (BZH), University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
4
Cell Networks, Bioquant, Ruprecht-Karl University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
5
Institute of Systems and Synthetic Biology, Genopole, CNRS, Université d'Evry, 91030 Evry, France.
6
Department of Molecular Epigenetics, Helmholtz Center Munich, Center for Integrated Protein Science, 81377 Munich, Germany.
7
Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA.
8
Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
9
German Center for Neurodegenerative Diseases (DZNE) within the Helmholz Association, Otfried-Müller Strasse 23, 72076 Tuebingen, Germany.
10
Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
11
Department of Otorhinolaryngology and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
12
Telethon Institute of Genetics and Medicine, TIGEM 80078, Italy.
13
Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
14
Cell and Matrix Biology, Inst. of Zoology, Johannes Gutenberg University of Mainz, 55122 Mainz, Germany.
15
Cambridge Cell Networks Ltd, St John's Innovation Centre, Cowley Road, Cambridge, CB4 0WS, UK.
16
Department of Translational Medicine Federico II University, 80131 Naples, Italy.
17
Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
18
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
19
Centre for Molecular and Biomolecular Informatics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6525 GA Nijmegen, The Netherlands.
20
School of Biomolecular &Biomed Science, Conway Institute, University College Dublin, Dublin 4, Ireland.

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.

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