8khp
CULLIN3-KLHL22-RBX1 E3 ligaseCULLIN3-KLHL22-RBX1 E3 ligase
Structural highlights
DiseaseKLH22_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] FunctionKLH22_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] Publication Abstract from PubMedCULLIN-RING ligases constitute the largest group of E3 ubiquitin ligases. While some CULLIN family members recruit adapters before engaging further with different substrate receptors, homo-dimeric BTB-Kelch family proteins combine adapter and substrate receptor into a single polypeptide for the CULLIN3 family. However, the entire structural assembly and molecular details have not been elucidated to date. Here, we present a cryo-EM structure of the CULLIN3(RBX1) in complex with Kelch-like protein 22 (KLHL22) and a mitochondrial glutamate dehydrogenase complex I (GDH1) at 3.06 A resolution. The structure adopts a W-shaped architecture formed by E3 ligase dimers. Three CULLIN3(KLHL22-RBX1) dimers were found to be dynamically associated with a single GDH1 hexamer. CULLIN3(KLHL22-RBX1) ligase mediated the polyubiquitination of GDH1 in vitro. Together, these results enabled the establishment of a structural model for understanding the complete assembly of BTB-Kelch proteins with CULLIN3 and how together they recognize oligomeric substrates and target them for ubiquitination. Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme.,Teng F, Wang Y, Liu M, Tian S, Stjepanovic G, Su MY Structure. 2023 Sep 22:S0969-2126(23)00325-8. doi: 10.1016/j.str.2023.09.002. PMID:37788672[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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