5zal

Cryo-EM structure of human Dicer and its complexes with a pre-miRNA substrateCryo-EM structure of human Dicer and its complexes with a pre-miRNA substrate

5zal, resolution 4.70Å Show:Asymmetric Unit Biological Assembly Structural highlights 5zal is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.7Å Experimental data: Check Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DICER_HUMAN Defects in DICER1 are a cause of pleuropulmonary blastoma (PPB) [MIM:601200. PPB is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome. PPBs contain both epithelial and mesenchymal cells. Early in tumorigenesis, cysts form in lung airspaces, and these cysts are lined with benign-appearing epithelium. Mesenchymal cells susceptible to malignant transformation reside within the cyst walls and form a dense 'cambium' layer beneath the epithelial lining. In a subset of patients, overgrowth of the mesenchymal cells produces a sarcoma, a transition that is associated with a poorer prognosis. Defects in DICER1 are the cause of goiter multinodular type 1 with or without Sertoli-Leydig cell tumors (MNG1) [MIM:138800. A common disorder characterized by nodular overgrowth of the thyroid gland. Some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary. Note=DICER1 mutations have been found in uterine cervix embryonal rhabdomyosarcoma, primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration and juvenile intestinal polyp (PubMed:21882293). Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. These mutations do not abolish DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic (PubMed:22187960). Function DICER_HUMAN Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Also cleaves double-stranded RNA to produce short interfering RNAs (siRNAs) which target the selective destruction of complementary RNAs. Publication Abstract from PubMed Human Dicer (hDicer) is a multi-domain protein belonging to the RNase III family. It plays pivotal roles in small RNA biogenesis during the RNA interference (RNAi) pathway by processing a diverse range of double-stranded RNA (dsRNA) precursors to generate approximately 22 nt microRNA (miRNA) or small interfering RNA (siRNA) products for sequence-directed gene silencing. In this work, we solved the cryoelectron microscopy (cryo-EM) structure of hDicer in complex with its cofactor protein TRBP and revealed the precise spatial arrangement of hDicer's multiple domains. We further solved structures of the hDicer-TRBP complex bound with pre-let-7 RNA in two distinct conformations. In combination with biochemical analysis, these structures reveal a property of the hDicer-TRBP complex to promote the stability of pre-miRNA's stem duplex in a pre-dicing state. These results provide insights into the mechanism of RNA processing by hDicer and illustrate the regulatory role of hDicer's N-terminal helicase domain. Cryo-EM Structure of Human Dicer and Its Complexes with a Pre-miRNA Substrate.,Liu Z, Wang J, Cheng H, Ke X, Sun L, Zhang QC, Wang HW Cell. 2018 May 17;173(5):1191-1203.e12. doi: 10.1016/j.cell.2018.03.080. Epub, 2018 Apr 26. PMID:29706542 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ribonuclease 3D structures