5udz

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Human LIN28A in complex with let-7f-1 microRNA pre-element

Structural highlights

5udz is a 4 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:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LN28A_HUMAN Acts as a 'translational enhancer', driving specific mRNAs to polysomes and thus increasing the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in stabilizing the mRNAs. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression (By similarity). Acts as a suppressor of microRNA (miRNA) biogenesis by specifically binding the precursor let-7 (pre-let-7), a miRNA precursor. Acts by binding pre-let-7 and recruiting ZCCHC11/TUT4 uridylyltransferase, leading to the terminal uridylation of pre-let-7. Uridylated pre-let-7 miRNAs fail to be processed by Dicer and undergo degradation. Degradation of pre-let-7 in embryonic stem (ES) cells contributes to the maintenance of ES cells. In contrast, LIN28A down-regulation in neural stem cells by miR-125, allows the processing of pre-let-7. Specifically recognizes the 5'-GGAG-3' motif in the terminal loop of pre-let-7. Also recognizes and binds non pre-let-7 pre-miRNAs that contain the 5'-GGAG-3' motif in the terminal loop, leading to their terminal uridylation and subsequent degradation.^[1] ^[2]

Publication Abstract from PubMed

LIN28 is an RNA binding protein that plays crucial roles in pluripotency, glucose metabolism, tissue regeneration, and tumorigenesis. LIN28 binds to the let-7 primary and precursor microRNAs through bipartite recognition and induces degradation of let-7 precursors (pre-let-7) by promoting oligouridylation by terminal uridylyltransferases (TUTases). Here, we report that the zinc knuckle domain (ZKD) of mouse LIN28 recruits TUT4 to initiate the oligouridylation of let-7 precursors. Our crystal structure of human LIN28 in complex with a fragment of pre-let-7f-1 determined to 2.0 A resolution shows that the interaction between ZKD and RNA is constrained to a small cavity with a high druggability score. We demonstrate that the specific interaction between ZKD and pre-let-7 is necessary and sufficient to induce oligouridylation by recruiting the N-terminal fragment of TUT4 (NTUT4) and the formation of a stable ZKD:NTUT4:pre-let-7 ternary complex is crucial for the acquired processivity of TUT4.

LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation.,Wang L, Nam Y, Lee AK, Yu C, Roth K, Chen C, Ransey EM, Sliz P Cell Rep. 2017 Mar 14;18(11):2664-2675. doi: 10.1016/j.celrep.2017.02.044. PMID:28297670^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008 Oct 24;32(2):276-84. doi: 10.1016/j.molcel.2008.09.014. PMID:18951094 doi:http://dx.doi.org/10.1016/j.molcel.2008.09.014
↑ Heo I, Joo C, Kim YK, Ha M, Yoon MJ, Cho J, Yeom KH, Han J, Kim VN. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell. 2009 Aug 21;138(4):696-708. doi: 10.1016/j.cell.2009.08.002. PMID:19703396 doi:http://dx.doi.org/10.1016/j.cell.2009.08.002
↑ Wang L, Nam Y, Lee AK, Yu C, Roth K, Chen C, Ransey EM, Sliz P. LIN28 Zinc Knuckle Domain Is Required and Sufficient to Induce let-7 Oligouridylation. Cell Rep. 2017 Mar 14;18(11):2664-2675. doi: 10.1016/j.celrep.2017.02.044. PMID:28297670 doi:http://dx.doi.org/10.1016/j.celrep.2017.02.044