An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
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...
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| Materyal Türü: | Journal article |
| Baskı/Yayın Bilgisi: |
Nature Publishing Group
2016
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| _version_ | 1826296722536529920 |
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| author | Boldt, K van Reeuwijk, J Lu, Q Koutroumpas, K Nguyen, T-MT Texier, Y van Beersum, SEC Horn, N Willer, JR Mans, DA Dougherty, G Lamers, IJC Coene, KLM Arts, HH Betts, MJ Beyer, T Bolat, E Gloeckner, CJ Haidari, K Hetterschijt, L Iaconis, D Jenkins, D Klose, F Knapp, B Latour, B Letteboer, SJF Marcelis, CL Mitic, D Morleo, M Oud, MM Riemersma, M Rix, S Terhal, PA Toedt, G van Dam, TJP de Vrieze, E Wissinger, Y Wu, KM Apic, G Beales, PL Blacque, OE Gibson, TJ Huynen, MA Katsanis, N Kremer, H Omran, H van Wijk, E Wolfrum, U Kepes, F Davis, EE Franco, B Giles, RH Ueffing, M Russell, RB Roepman, R 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 Franklin, C Futema, M Humphries, SE Hurles, M Joyce, C McCarthy, S Mitchison, HM Muddyman, D Muntoni, F O'Rahilly, S Onoufriadis, A Payne, F Plagnol, V Raymond, L Savage, DB Scambler, P Schmidts, M Schoenmakers, N Semple, R Serra, E Stalker, J van Kogelenberg, M Vijayarangakannan, P Walter, K Whittall, R Williamson, K |
| author_facet | Boldt, K van Reeuwijk, J Lu, Q Koutroumpas, K Nguyen, T-MT Texier, Y van Beersum, SEC Horn, N Willer, JR Mans, DA Dougherty, G Lamers, IJC Coene, KLM Arts, HH Betts, MJ Beyer, T Bolat, E Gloeckner, CJ Haidari, K Hetterschijt, L Iaconis, D Jenkins, D Klose, F Knapp, B Latour, B Letteboer, SJF Marcelis, CL Mitic, D Morleo, M Oud, MM Riemersma, M Rix, S Terhal, PA Toedt, G van Dam, TJP de Vrieze, E Wissinger, Y Wu, KM Apic, G Beales, PL Blacque, OE Gibson, TJ Huynen, MA Katsanis, N Kremer, H Omran, H van Wijk, E Wolfrum, U Kepes, F Davis, EE Franco, B Giles, RH Ueffing, M Russell, RB Roepman, R 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 Franklin, C Futema, M Humphries, SE Hurles, M Joyce, C McCarthy, S Mitchison, HM Muddyman, D Muntoni, F O'Rahilly, S Onoufriadis, A Payne, F Plagnol, V Raymond, L Savage, DB Scambler, P Schmidts, M Schoenmakers, N Semple, R Serra, E Stalker, J van Kogelenberg, M Vijayarangakannan, P Walter, K Whittall, R Williamson, K |
| author_sort | Boldt, K |
| collection | OXFORD |
| 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 sh ows considerable promise for Systems Medicine. |
| first_indexed | 2024-03-07T04:20:43Z |
| format | Journal article |
| id | oxford-uuid:caec74e1-9769-4049-8f27-7acb51d09a31 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T04:20:43Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:caec74e1-9769-4049-8f27-7acb51d09a312022-03-27T07:11:18ZAn organelle-specific protein landscape identifies novel diseases and molecular mechanismsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:caec74e1-9769-4049-8f27-7acb51d09a31Symplectic Elements at OxfordNature Publishing Group2016Boldt, Kvan Reeuwijk, JLu, QKoutroumpas, KNguyen, T-MTTexier, Yvan Beersum, SECHorn, NWiller, JRMans, DADougherty, GLamers, IJCCoene, KLMArts, HHBetts, MJBeyer, TBolat, EGloeckner, CJHaidari, KHetterschijt, LIaconis, DJenkins, DKlose, FKnapp, BLatour, BLetteboer, SJFMarcelis, CLMitic, DMorleo, MOud, MMRiemersma, MRix, STerhal, PAToedt, Gvan Dam, TJPde Vrieze, EWissinger, YWu, KMApic, GBeales, PLBlacque, OEGibson, TJHuynen, MAKatsanis, NKremer, HOmran, Hvan Wijk, EWolfrum, UKepes, FDavis, EEFranco, BGiles, RHUeffing, MRussell, RBRoepman, RAl-Turki, SAnderson, CAntony, DBarroso, IBentham, JBhattacharya, SCarss, KChatterjee, KCirak, SCosgrove, CDanecek, PDurbin, RFitzpatrick, DFloyd, JFoley, AFranklin, CFutema, MHumphries, SEHurles, MJoyce, CMcCarthy, SMitchison, HMMuddyman, DMuntoni, FO'Rahilly, SOnoufriadis, APayne, FPlagnol, VRaymond, LSavage, DBScambler, PSchmidts, MSchoenmakers, NSemple, RSerra, EStalker, Jvan Kogelenberg, MVijayarangakannan, PWalter, KWhittall, RWilliamson, KCellular 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 sh ows considerable promise for Systems Medicine. |
| spellingShingle | Boldt, K van Reeuwijk, J Lu, Q Koutroumpas, K Nguyen, T-MT Texier, Y van Beersum, SEC Horn, N Willer, JR Mans, DA Dougherty, G Lamers, IJC Coene, KLM Arts, HH Betts, MJ Beyer, T Bolat, E Gloeckner, CJ Haidari, K Hetterschijt, L Iaconis, D Jenkins, D Klose, F Knapp, B Latour, B Letteboer, SJF Marcelis, CL Mitic, D Morleo, M Oud, MM Riemersma, M Rix, S Terhal, PA Toedt, G van Dam, TJP de Vrieze, E Wissinger, Y Wu, KM Apic, G Beales, PL Blacque, OE Gibson, TJ Huynen, MA Katsanis, N Kremer, H Omran, H van Wijk, E Wolfrum, U Kepes, F Davis, EE Franco, B Giles, RH Ueffing, M Russell, RB Roepman, R 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 Franklin, C Futema, M Humphries, SE Hurles, M Joyce, C McCarthy, S Mitchison, HM Muddyman, D Muntoni, F O'Rahilly, S Onoufriadis, A Payne, F Plagnol, V Raymond, L Savage, DB Scambler, P Schmidts, M Schoenmakers, N Semple, R Serra, E Stalker, J van Kogelenberg, M Vijayarangakannan, P Walter, K Whittall, R Williamson, K An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title | An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title_full | An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title_fullStr | An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title_full_unstemmed | An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title_short | An organelle-specific protein landscape identifies novel diseases and molecular mechanisms |
| title_sort | organelle specific protein landscape identifies novel diseases and molecular mechanisms |
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