2n8l
From Proteopedia
Zipcode-binding-protein-1 KH3KH4(DD) domains in complex with the KH3 RNA target
Structural highlights
Function[IF2B1_CHICK] RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation. Plays a direct role in the transport and translation of transcripts required for axonal regeneration in adult sensory neurons (By similarity). Regulates localized beta-actin/ACTB mRNA translation in polarized cells, a crucial process for cell migration and neurite outgrowth. Co-transcriptionally associates with the ACTB mRNA in the nucleus. This binding involves by a conserved 54-nucleotide element in the ACTB mRNA 3'-UTR, known as the 'zipcode'. The ribonucleoparticle (RNP) thus formed is exported to the cytoplasm, binds to a motor protein and is transported along the cytoskeleton to the cell periphery. During transport, IGF2BP1 prevents beta-actin mRNA from being translated into protein. When the RNP complex reaches its destination near the plasma membrane, IGF2BP1 is phosphorylated by SRC. This releases the mRNA, allowing ribosomal 40S and 60S subunits to assemble and initiate ACTB protein synthesis. The monomeric ACTB protein then assembles into the subcortical actin cytoskeleton, which pushes the leading edge onwards. Binds MYC mRNA. Promotes the directed movement of cells by fine-tuning intracellular signaling networks. Binds to MAPK4 3'-UTR and inhibits its translation. Interacts with PTEN transcript open reading frame (ORF) and prevents mRNA decay. This combined action on MAPK4 (down-regulation) and PTEN (up-regulation) antagonizes HSPB1 phosphorylation, consequently it prevents G-actin sequestration by phosphorylated HSPB1, allowing F-actin polymerization. Hence enhances the velocity of cell migration and stimulates directed cell migration by PTEN-modulated polarization.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedZBP1 (zipcode-binding protein 1) was originally discovered as a trans-acting factor for the "zipcode" in the 3' untranslated region (UTR) of the beta-actin mRNA that is important for its localization and translational regulation. Subsequently, ZBP1 has been found to be a multifunctional regulator of RNA metabolism that controls aspects of localization, stability, and translation for many mRNAs. To reveal how ZBP1 recognizes its RNA targets, we biochemically characterized the interaction between ZBP1 and the beta-actin zipcode. The third and fourth KH (hnRNP K homology) domains of ZBP1 specifically recognize a bipartite RNA element located within the first 28 nucleotides of the zipcode. The spacing between the RNA sequences is consistent with the structure of IMP1 KH34, the human ortholog of ZBP1, that we solved by X-ray crystallography. The tandem KH domains are arranged in an intramolecular anti-parallel pseudodimer conformation with the canonical RNA-binding surfaces at opposite ends of the molecule. This orientation of the KH domains requires that the RNA backbone must undergo an approximately 180 degrees change in direction in order for both KH domains to contact the RNA simultaneously. The RNA looping induced by ZBP1 binding provides a mechanism for specific recognition and may facilitate the assembly of post-transcriptional regulatory complexes by remodeling the bound transcript. ZBP1 recognition of beta-actin zipcode induces RNA looping.,Chao JA, Patskovsky Y, Patel V, Levy M, Almo SC, Singer RH Genes Dev. 2010 Jan 15;24(2):148-58. PMID:20080952[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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