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| | <StructureSection load='6lt0' size='340' side='right'caption='[[6lt0]], [[Resolution|resolution]] 3.20Å' scene=''> | | <StructureSection load='6lt0' size='340' side='right'caption='[[6lt0]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6lt0]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LT0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6LT0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6lt0]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LT0 FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">WDR41, MSTP048 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SMCR8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), C9orf72 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6lt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lt0 OCA], [http://pdbe.org/6lt0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6lt0 RCSB], [http://www.ebi.ac.uk/pdbsum/6lt0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6lt0 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6lt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lt0 OCA], [https://pdbe.org/6lt0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lt0 RCSB], [https://www.ebi.ac.uk/pdbsum/6lt0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lt0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/CI072_HUMAN CI072_HUMAN]] Progressive non-fluent aphasia;Frontotemporal dementia with motor neuron disease;Amyotrophic lateral sclerosis;Huntington disease-like syndrome due to C9ORF72 expansions;Semantic dementia;Behavioral variant of frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death (PubMed:24598541). The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) -- poly-GA, poly-GP, poly-GR, poly-PA and poly-PR -- via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion (PubMed:24132570).<ref>PMID:24132570</ref> <ref>PMID:24598541</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/WDR41_HUMAN WDR41_HUMAN]] Non-catalytic component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27103069, PubMed:27617292).<ref>PMID:27103069</ref> <ref>PMID:27193190</ref> <ref>PMID:27617292</ref> <ref>PMID:28195531</ref> [[http://www.uniprot.org/uniprot/CI072_HUMAN CI072_HUMAN]] Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity (PubMed:27617292). Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation (PubMed:27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131). Plays a role in endosomal trafficking (PubMed:24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PubMed:27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation (PubMed:27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity).[UniProtKB:Q6DFW0]<ref>PMID:24549040</ref> <ref>PMID:27103069</ref> <ref>PMID:27193190</ref> <ref>PMID:27334615</ref> <ref>PMID:27559131</ref> <ref>PMID:27617292</ref> <ref>PMID:27723745</ref> <ref>PMID:28195531</ref> Regulates stress granule assembly in response to cellular stress.<ref>PMID:27037575</ref> Does not play a role in regulation of stress granule assembly in response to cellular stress.<ref>PMID:27037575</ref> [[http://www.uniprot.org/uniprot/SMCR8_HUMAN SMCR8_HUMAN]] Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:20562859, PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:20562859, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27617292, PubMed:28195531). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131, PubMed:28195531). In addition to its activity in the cytoplasm within the C9orf72-SMCR8 complex, SMCR8 also localizes in the nucleus, where it associates with chromatin and negatively regulates expression of suppresses ULK1 and WIPI2 genes (PubMed:28195531).<ref>PMID:20562859</ref> <ref>PMID:27103069</ref> <ref>PMID:27193190</ref> <ref>PMID:27559131</ref> <ref>PMID:27617292</ref> <ref>PMID:28195531</ref> | + | [https://www.uniprot.org/uniprot/WDR41_HUMAN WDR41_HUMAN] Non-catalytic component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27103069, PubMed:27617292).<ref>PMID:27103069</ref> <ref>PMID:27193190</ref> <ref>PMID:27617292</ref> <ref>PMID:28195531</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72-SMCR8-WDR41 complex at a resolution of 3.2 A. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72-SMCR8-WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72-SMCR8-WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72-SMCR8 resembles that of the FLNC-FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72-SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72-SMCR8-WDR41 complex assembly but also reveals the GAP activity of the C9ORF72-SMCR8 complex.
| + | |
| | | | |
| - | Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a.,Tang D, Sheng J, Xu L, Zhan X, Liu J, Jiang H, Shu X, Liu X, Zhang T, Jiang L, Zhou C, Li W, Cheng W, Li Z, Wang K, Lu K, Yan C, Qi S Proc Natl Acad Sci U S A. 2020 Apr 17. pii: 2002110117. doi:, 10.1073/pnas.2002110117. PMID:32303654<ref>PMID:32303654</ref>
| + | ==See Also== |
| - | | + | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6lt0" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Qi, S]] | + | [[Category: Qi S]] |
| - | [[Category: Sheng, J]] | + | [[Category: Sheng J]] |
| - | [[Category: Tang, D]] | + | [[Category: Tang D]] |
| - | [[Category: Xu, L]] | + | [[Category: Xu L]] |
| - | [[Category: Yan, C]] | + | [[Category: Yan C]] |
| - | [[Category: Zhan, X]] | + | [[Category: Zhan X]] |
| - | [[Category: Al]]
| + | |
| - | [[Category: C9orf72]]
| + | |
| - | [[Category: Ftd]]
| + | |
| - | [[Category: Gap]]
| + | |
| - | [[Category: Gef]]
| + | |
| - | [[Category: Gtpase]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Smcr8]]
| + | |
| - | [[Category: Wdr41]]
| + | |
| Structural highlights
Function
WDR41_HUMAN Non-catalytic component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:27103069). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and inhibiting its protein kinase activity (PubMed:27103069, PubMed:27617292).[1] [2] [3] [4]
See Also
References
- ↑ Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, Ruffenach F, Page A, Ciura S, Kabashi E, Charlet-Berguerand N. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016 Jun 15;35(12):1276-97. doi: 10.15252/embj.201593350. Epub 2016 Apr, 21. PMID:27103069 doi:http://dx.doi.org/10.15252/embj.201593350
- ↑ Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, Smolka MB, Hu F. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun. 2016 May 18;4(1):51. doi: 10.1186/s40478-016-0324-5. PMID:27193190 doi:http://dx.doi.org/10.1186/s40478-016-0324-5
- ↑ Yang M, Liang C, Swaminathan K, Herrlinger S, Lai F, Shiekhattar R, Chen JF. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016 Sep 2;2(9):e1601167. doi: 10.1126/sciadv.1601167. eCollection 2016 , Sep. PMID:27617292 doi:http://dx.doi.org/10.1126/sciadv.1601167
- ↑ Jung J, Nayak A, Schaeffer V, Starzetz T, Kirsch AK, Muller S, Dikic I, Mittelbronn M, Behrends C. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator. Elife. 2017 Feb 14;6. doi: 10.7554/eLife.23063. PMID:28195531 doi:http://dx.doi.org/10.7554/eLife.23063
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