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==Cryo-EM structure of human Dicer and its complexes with a pre-miRNA substrate== | |||
<StructureSection load='5zal' size='340' side='right' caption='[[5zal]], [[Resolution|resolution]] 4.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5zal]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZAL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZAL FirstGlance]. <br> | |||
</td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ribonuclease_III Ribonuclease III], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.26.3 3.1.26.3] </span></td></tr> | |||
[[Category: | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zal FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zal OCA], [http://pdbe.org/5zal PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zal RCSB], [http://www.ebi.ac.uk/pdbsum/5zal PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zal ProSAT]</span></td></tr> | ||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/DICER_HUMAN DICER_HUMAN]] Defects in DICER1 are a cause of pleuropulmonary blastoma (PPB) [MIM:[http://omim.org/entry/601200 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.<ref>PMID:21882293</ref> <ref>PMID:19556464</ref> Defects in DICER1 are the cause of goiter multinodular type 1 with or without Sertoli-Leydig cell tumors (MNG1) [MIM:[http://omim.org/entry/138800 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.<ref>PMID:21882293</ref> <ref>PMID:21205968</ref> 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).<ref>PMID:21882293</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/DICER_HUMAN 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.<ref>PMID:15242644</ref> <ref>PMID:16271387</ref> <ref>PMID:16289642</ref> <ref>PMID:16142218</ref> <ref>PMID:16357216</ref> <ref>PMID:15973356</ref> <ref>PMID:16424907</ref> <ref>PMID:17452327</ref> <ref>PMID:18178619</ref> <ref>PMID:19219043</ref> [[http://www.uniprot.org/uniprot/TRBP2_HUMAN TRBP2_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. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1. Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs. This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha. May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR.<ref>PMID:12475984</ref> <ref>PMID:16271387</ref> <ref>PMID:16142218</ref> <ref>PMID:16357216</ref> <ref>PMID:15973356</ref> <ref>PMID:16424907</ref> <ref>PMID:17452327</ref> <ref>PMID:18178619</ref> <ref>PMID:19219043</ref> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Ribonuclease III]] | |||
[[Category: Cheng, H]] | |||
[[Category: Ke, X]] | |||
[[Category: Liu, Z]] | [[Category: Liu, Z]] | ||
[[Category: | [[Category: Sun, L]] | ||
[[Category: Wang, H W]] | |||
[[Category: Wang, H | |||
[[Category: Wang, J]] | [[Category: Wang, J]] | ||
[[Category: | [[Category: Zhang, Q C]] | ||
[[Category: | [[Category: Cryo-em]] | ||
[[Category: Dicer]] | |||
[[Category: Hydrolase-protein binding-rna complex]] | |||
[[Category: Protein binding]] | |||
[[Category: Rna interference]] | |||
[[Category: Trbp]] | |||