Structure of the Fanconi anaemia monoubiquitin ligase complex
| العنوان: | Structure of the Fanconi anaemia monoubiquitin ligase complex |
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| المؤلفون: | Shabih Shakeel, Christopher J. Russo, Gianluca Degliesposti, Pablo Alcón, Eeson Rajendra, J.M. Skehel, Ketan J. Patel, Sarah L. Maslen, Carol V. Robinson, Chris H. Hill, Dror S. Chorev, Francis J. O’Reilly, Juri Rappsilber, Shaoda He, Sjors H.W. Scheres, Lori A. Passmore |
| المصدر: | Shakeel, S, Rajendral, E, Alcón, P, O’Reilly, F J, Chorev, D S, Maslen, S, Degliesposti, G, Russo, C J, He, S, Hill, C H, Skehel, J M, Scheres, S H W, Patel, K J, Rappsilber, J, Robinson, C V & Passmore, L A 2019, ' Structure of the fanconi anaemia monoubiquitin ligase complex ', Nature, vol. 575, pp. 234-237 . https://doi.org/10.1038/s41586-019-1703-4 Nature |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Models, Molecular, Protein subunit, Fanconi Anemia Complementation Group L Protein, medicine.disease_cause, Article, Mass Spectrometry, Ligases, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, FANCD2, Ring finger, medicine, Humans, Animals, FANCL, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, DNA ligase, Mutation, Multidisciplinary, biology, Fanconi Anemia Complementation Group D2 Protein, Cryoelectron Microscopy, Ubiquitination, Fanconi Anemia Complementation Group Proteins, Ubiquitin ligase, Cell biology, FANCB, Protein Subunits, Fanconi Anemia, medicine.anatomical_structure, chemistry, Multiprotein Complexes, biology.protein, Protein Multimerization, Chickens, 030217 neurology & neurosurgery |
| الوصف: | The Fanconi anaemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress1,2. Genetic inactivation of this pathway by mutation of genes encoding FA complementation group (FANC) proteins impairs development, prevents blood production and promotes cancer1,3. The key molecular step in the FA pathway is the monoubiquitination of a pseudosymmetric heterodimer of FANCD2–FANCI4,5 by the FA core complex—a megadalton multiprotein E3 ubiquitin ligase6,7. Monoubiquitinated FANCD2 then recruits additional protein factors to remove the DNA crosslink or to stabilize the stalled replication fork. A molecular structure of the FA core complex would explain how it acts to maintain genome stability. Here we reconstituted an active, recombinant FA core complex, and used cryo-electron microscopy and mass spectrometry to determine its structure. The FA core complex comprises two central dimers of the FANCB and FA-associated protein of 100 kDa (FAAP100) subunits, flanked by two copies of the RING finger subunit, FANCL. These two heterotrimers act as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a non-functional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The two FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. This structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. The cryo-electron microscopy structure of the FA core complex provides a foundation for a detailed understanding of its E3 ubiquitin ligase activity and DNA interstrand crosslink repair. The structure of the multiprotein Fanconi anaemia core complex, determined using cryo-electron microscopy and mass spectrometry, shows that the complex adopts an extended asymmetric structure and highlights the structural and functional asymmetry of the RING finger domains. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-019-1703-4 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::46bffaa0a6d75638ea3668a8eca98bf3 https://doi.org/10.1038/s41586-019-1703-4 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....46bffaa0a6d75638ea3668a8eca98bf3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764687 00280836 |
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| DOI: | 10.1038/s41586-019-1703-4 |