6v4u

Structural highlights

Function

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).^{[1] [2] [3] [4] [5] [6]}

See Also

• WD-repeat protein 3D structures

References

1. ↑ Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature. 2010 Jul 1;466(7302):68-76. doi: 10.1038/nature09204. Epub 2010 Jun 20. PMID:20562859 doi:http://dx.doi.org/10.1038/nature09204
2. ↑ 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
3. ↑ 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
4. ↑ Amick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell. 2016 Oct 15;27(20):3040-3051. doi: 10.1091/mbc.E16-01-0003. Epub, 2016 Aug 24. PMID:27559131 doi:http://dx.doi.org/10.1091/mbc.E16-01-0003
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
6. ↑ 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