6qey

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IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties

Structural highlights

6qey is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:CCN, PO4
Gene:IGF2BP1, CRDBP, VICKZ1, ZBP1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[IF2B1_HUMAN] RNA-binding factor that affects mRNA nuclear export, localization, stability and translation. Component of the CRD-mediated complex that promotes MYC mRNA stabilization. Regulates mRNA stability during the integrated cellular stress response (ISR) in stress granules (SGs). Stabilizes the BTRC/FBW1A mRNA from degradation by disrupting miRNA-dependent interaction with AGO2. Identified in a HCV IRES-mediated translation complex, that enhances translation at the Hepatitis C virus (HCV) RNA-replicon via the internal ribosome entry site (IRES), but does not affect 5'cap-dependent translation. Acts as a HIV-1 retrovirus restriction factor that reduces HIV-1 assembly by inhibiting viral RNA packaging, assembly and processing of HIV-1 GAG protein on cellular membranes. Binds to mRNAs in stress granules (SGs). Binds to the stem-loop IV of the 5'-UTR and to the variable region and the poly(U-C) motif of the 3'-UTR of the HCV RNA-replicon. Binds to the 5'-UTR of the insulin-like growth factor 2 (IGF2) mRNA and regulates its subcellular localization and translation. Binds both to the coding region mRNA stability determinant (CRD) and to AU-rich sequences in the 3'-UTR of the MYC and CD44 mRNAs and stabilizes these mRNAs. Binds to the fourth and fifth exons of the oncofetal H19 and neuron-specific TAU mRNAs and regulates their localizations. Binds to the adenine-rich autoregulatory sequence (ARS) 5'-UTR of the PABPC1 mRNA and is involved in its translational repression. The RNA-binding activity to ARS is stimulated by PABPC1. Binds to the coding sequence region of BTRC/FBW1A mRNA and mediates stabilization of BTRC/FBW1A and MYC mRNAs in response to beta-catenin signaling. Binding to RNA employs a cooperative, sequential mechanism of homo- or heterodimerisation. Also involved in growth or survival of lung-cancer cells. Protects the MYC and MDR-1 mRNAs from cleavage by a endoribonuclease, thus prolonging their stabilities (By similarity). Binds to the 3'-UTR axonal localization signal (ALS) of TAU mRNA (By similarity). Binds to a conserved 54-nucleotide element in the 3'-UTR of the beta actin mRNA known as the 'zipcode' (By similarity). Promotes translocation of the beta-actin mRNA to dendrites (By similarity). May act as a regulator of mRNA transport to activated synapses in response to synaptic activity (By similarity).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

Publication Abstract from PubMed

IGF2 mRNA-binding protein 1 (IMP1) is a key regulator of messenger RNA (mRNA) metabolism and transport in organismal development and, in cancer, its mis-regulation is an important component of tumour metastasis. IMP1 function relies on the recognition of a diverse set of mRNA targets that is mediated by the combinatorial action of multiple RNA-binding domains. Here, we dissect the structure and RNA-binding properties of two key RNA-binding domains of IMP1, KH1 and KH2, and we build a kinetic model for the recognition of RNA targets. Our data and model explain how the two domains are organized as an intermolecular pseudo-dimer and that the important role they play in mRNA target recognition is underpinned by the high RNA-binding affinity and fast kinetics of this KH1KH2-RNA recognition unit. Importantly, the high-affinity RNA-binding by KH1KH2 is achieved by an inter-domain coupling 50-fold stronger than that existing in a second pseudo-dimer in the protein, KH3KH4. The presence of this strong coupling supports a role of RNA re-modelling in IMP1 recognition of known cancer targets.

IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties.,Dagil R, Ball NJ, Ogrodowicz RW, Hobor F, Purkiss AG, Kelly G, Martin SR, Taylor IA, Ramos A Nucleic Acids Res. 2019 Mar 13. pii: 5377473. doi: 10.1093/nar/gkz136. PMID:30864660[16]

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

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References

  1. ↑ Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol. 1999 Feb;19(2):1262-70. PMID:9891060
  2. ↑ Patel GP, Ma S, Bag J. The autoregulatory translational control element of poly(A)-binding protein mRNA forms a heteromeric ribonucleoprotein complex. Nucleic Acids Res. 2005 Dec 14;33(22):7074-89. Print 2005. PMID:16356927 doi:33/22/7074
  3. ↑ Prokipcak RD, Herrick DJ, Ross J. Purification and properties of a protein that binds to the C-terminal coding region of human c-myc mRNA. J Biol Chem. 1994 Mar 25;269(12):9261-9. PMID:8132663
  4. ↑ Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer UM, Christiansen J. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J Biol Chem. 2000 Sep 22;275(38):29562-9. PMID:10875929 doi:10.1074/jbc.M001156200
  5. ↑ Lemm I, Ross J. Regulation of c-myc mRNA decay by translational pausing in a coding region instability determinant. Mol Cell Biol. 2002 Jun;22(12):3959-69. PMID:12024010
  6. ↑ Vikesaa J, Hansen TV, Jonson L, Borup R, Wewer UM, Christiansen J, Nielsen FC. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 2006 Apr 5;25(7):1456-68. Epub 2006 Mar 16. PMID:16541107 doi:7601039
  7. ↑ Stohr N, Lederer M, Reinke C, Meyer S, Hatzfeld M, Singer RH, Huttelmaier S. ZBP1 regulates mRNA stability during cellular stress. J Cell Biol. 2006 Nov 20;175(4):527-34. Epub 2006 Nov 13. PMID:17101699 doi:10.1083/jcb.200608071
  8. ↑ Noubissi FK, Elcheva I, Bhatia N, Shakoori A, Ougolkov A, Liu J, Minamoto T, Ross J, Fuchs SY, Spiegelman VS. CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling. Nature. 2006 Jun 15;441(7095):898-901. PMID:16778892 doi:nature04839
  9. ↑ Kato T, Hayama S, Yamabuki T, Ishikawa N, Miyamoto M, Ito T, Tsuchiya E, Kondo S, Nakamura Y, Daigo Y. Increased expression of insulin-like growth factor-II messenger RNA-binding protein 1 is associated with tumor progression in patients with lung cancer. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):434-42. PMID:17255263 doi:13/2/434
  10. ↑ Pan F, Huttelmaier S, Singer RH, Gu W. ZBP2 facilitates binding of ZBP1 to beta-actin mRNA during transcription. Mol Cell Biol. 2007 Dec;27(23):8340-51. Epub 2007 Sep 24. PMID:17893325 doi:10.1128/MCB.00972-07
  11. ↑ Zhou Y, Rong L, Lu J, Pan Q, Liang C. Insulin-like growth factor II mRNA binding protein 1 associates with Gag protein of human immunodeficiency virus type 1, and its overexpression affects virus assembly. J Virol. 2008 Jun;82(12):5683-92. doi: 10.1128/JVI.00189-08. Epub 2008 Apr 2. PMID:18385235 doi:10.1128/JVI.00189-08
  12. ↑ Elcheva I, Goswami S, Noubissi FK, Spiegelman VS. CRD-BP protects the coding region of betaTrCP1 mRNA from miR-183-mediated degradation. Mol Cell. 2009 Jul 31;35(2):240-6. doi: 10.1016/j.molcel.2009.06.007. PMID:19647520 doi:10.1016/j.molcel.2009.06.007
  13. ↑ Weidensdorfer D, Stohr N, Baude A, Lederer M, Kohn M, Schierhorn A, Buchmeier S, Wahle E, Huttelmaier S. Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA. 2009 Jan;15(1):104-15. doi: 10.1261/rna.1175909. Epub 2008 Nov 24. PMID:19029303 doi:10.1261/rna.1175909
  14. ↑ Weinlich S, Huttelmaier S, Schierhorn A, Behrens SE, Ostareck-Lederer A, Ostareck DH. IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3'UTR. RNA. 2009 Aug;15(8):1528-42. doi: 10.1261/rna.1578409. Epub 2009 Jun 18. PMID:19541769 doi:10.1261/rna.1578409
  15. ↑ Chao JA, Patskovsky Y, Patel V, Levy M, Almo SC, Singer RH. ZBP1 recognition of beta-actin zipcode induces RNA looping. Genes Dev. 2010 Jan 15;24(2):148-58. PMID:20080952 doi:24/2/148
  16. ↑ Dagil R, Ball NJ, Ogrodowicz RW, Hobor F, Purkiss AG, Kelly G, Martin SR, Taylor IA, Ramos A. IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties. Nucleic Acids Res. 2019 Mar 13. pii: 5377473. doi: 10.1093/nar/gkz136. PMID:30864660 doi:http://dx.doi.org/10.1093/nar/gkz136

Contents


PDB ID 6qey

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