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An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
- Source :
- Nature Communications 7(1), 11491 (2016). doi:10.1038/ncomms11491, Boldt, K, Van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, T M 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, 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, 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, Foley, A R, 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, 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, Russell, R B & Roepman, R 2016, ' An organelle-specific protein landscape identifies novel diseases and molecular mechanisms ', Nature Communications, vol. 7, 11491 . https://doi.org/10.1038/ncomms11491, Nat. Commun. 7:11491 (2016), Nature Communications, Nature Communications, 7, 11491-11491, Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016), Nature Communications, 7, pp. 11491-11491
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group UK, 2016.
-
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.<br />Mutations in proteins that localize to primary cilia cause devastating diseases, yet the primary cilium is a poorly understood organelle. Here the authors use interaction proteomics to identify a network of human ciliary proteins that provides new insights into several biological processes and diseases.
- Subjects :
- Proteomics
0301 basic medicine
Systems Analysis
DNA Mutational Analysis
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
General Physics and Astronomy
Datasets as Topic
methods [Chromatography, Affinity]
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Chromatography, Affinity
Mass Spectrometry
Protein Interaction Mapping
therapy [Ciliopathies]
genetics [Ciliopathies]
methods [Molecular Targeted Therapy]
Molecular Targeted Therapy
Protein Interaction Maps
Multidisciplinary
Cilium
Chemistry (all)
abnormalities [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 health
Cell biology
Vesicular transport protein
pathology [Dwarfism]
metabolism [Cilia]
Muscle Hypotonia
ddc:500
pathology [Muscle Hypotonia]
pathology [Spine]
genetics [Dwarfism]
Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Science
Dwarfism
Exocyst
Biology
Article
General Biochemistry, Genetics and Molecular Biology
Physics and Astronomy (all)
03 medical and health sciences
Intraflagellar transport
Ciliogenesis
Organelle
Humans
Cilia
Biochemistry, Genetics and Molecular Biology (all)
Proteins
Biological Transport
General Chemistry
therapy [Dwarfism]
Fibroblasts
genetics [Proteins]
Ciliopathies
Spine
methods [Protein Interaction Mapping]
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
030104 developmental biology
Proteostasis
HEK293 Cells
methods [Proteomics]
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications 7(1), 11491 (2016). doi:10.1038/ncomms11491, Boldt, K, Van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, T M 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, 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, 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, Foley, A R, 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, 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, Russell, R B & Roepman, R 2016, ' An organelle-specific protein landscape identifies novel diseases and molecular mechanisms ', Nature Communications, vol. 7, 11491 . https://doi.org/10.1038/ncomms11491, Nat. Commun. 7:11491 (2016), Nature Communications, Nature Communications, 7, 11491-11491, Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016), Nature Communications, 7, pp. 11491-11491
- Accession number :
- edsair.doi.dedup.....ed822a01064aab67a40c84234dc2fc74