8khp

Structural highlights

Disease

KLH22_HUMAN Defects in KLHL22 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.^[1]

Function

KLH22_HUMAN Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for chromosome alignment and localization of PLK1 at kinetochores. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. Monoubiquitination of PLK1 does not lead to PLK1 degradation (PubMed:19995937, PubMed:23455478). The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated 'Lys-48' polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. It is therefore an amino acid-dependent activator within the amino acid-sensing branch of the TORC1 pathway, indirectly regulating different cellular processes including cell growth and autophagy (PubMed:29769719).^{[2] [3] [4]}

See Also

• Ubiquitin protein ligase 3D structures

References

1. ↑ Rainger J, Williamson KA, Soares DC, Truch J, Kurian D, Gillessen-Kaesbach G, Seawright A, Prendergast J, Halachev M, Wheeler A, McTeir L, Gill AC, van Heyningen V, Davey MG, FitzPatrick DR. A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma. Hum Mutat. 2017 Aug;38(8):942-946. PMID:28493397 doi:10.1002/humu.23246
2. ↑ Maerki S, Olma MH, Staubli T, Steigemann P, Gerlich DW, Quadroni M, Sumara I, Peter M. The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone microtubules in anaphase and is required for cytokinesis. J Cell Biol. 2009 Dec 14;187(6):791-800. PMID:19995937 doi:10.1083/jcb.200906117
3. ↑ Beck J, Maerki S, Posch M, Metzger T, Persaud A, Scheel H, Hofmann K, Rotin D, Pedrioli P, Swedlow JR, Peter M, Sumara I. Ubiquitylation-dependent localization of PLK1 in mitosis. Nat Cell Biol. 2013 Apr;15(4):430-9. PMID:23455478 doi:10.1038/ncb2695
4. ↑ Chen J, Ou Y, Yang Y, Li W, Xu Y, Xie Y, Liu Y. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature. 2018 May;557(7706):585-589. PMID:29769719 doi:10.1038/s41586-018-0128-9