| Structural highlights
Function
LARP1_HUMAN RNA-binding protein that promotes translation of specific classes of mRNAs downstream of the mTORC1 complex. Associates with the mRNA 5'cap in an MTOR-dependent manner and associates with mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding for ribosomal proteins and several components of the translation machinery. Associates with actively translating ribosomes via interaction with PABPC1/PABP and stimulates translation of mRNAs containing a 5'TOP, thereby regulating cell growth and proliferation.[1] [2] [3]
Publication Abstract from PubMed
La-related proteins (LARPs) comprise a family of RNA-binding proteins involved in a wide range of posttranscriptional regulatory activities. LARPs share a unique tandem of two RNA-binding domains, La motif (LaM) and RNA recognition motif (RRM), together referred to as a La-module, but vary in member-specific regions. Prior structural studies of La-modules reveal they are pliable platforms for RNA recognition in diverse contexts. Here, we characterize the La-module of LARP1, which plays an important role in regulating synthesis of ribosomal proteins in response to mTOR signaling and mRNA stabilization. LARP1 has been well characterized functionally but no structural information exists for its La-module. We show that unlike other LARPs, the La-module in LARP1 does not contain an RRM domain. The LaM alone is sufficient for binding poly(A) RNA with submicromolar affinity and specificity. Multiple high-resolution crystal structures of the LARP1 LaM domain in complex with poly(A) show that it is highly specific for the RNA 3'-end, and identify LaM residues Q333, Y336 and F348 as the most critical for binding. Use of a quantitative mRNA stabilization assay and poly(A) tail-sequencing demonstrate functional relevance of LARP1 RNA binding in cells and provide novel insight into its poly(A) 3' protection activity.
Structural basis of 3'-end poly(A) RNA recognition by LARP1.,Kozlov G, Mattijssen S, Jiang J, Nyandwi S, Sprules T, Iben JR, Coon SL, Gaidamakov S, Noronha AM, Wilds CJ, Maraia RJ, Gehring K Nucleic Acids Res. 2022 Aug 18. pii: 6671114. doi: 10.1093/nar/gkac696. PMID:35979957[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Burrows C, Abd Latip N, Lam SJ, Carpenter L, Sawicka K, Tzolovsky G, Gabra H, Bushell M, Glover DM, Willis AE, Blagden SP. The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration. Nucleic Acids Res. 2010 Sep;38(16):5542-53. doi: 10.1093/nar/gkq294. Epub 2010, Apr 29. PMID:20430826 doi:http://dx.doi.org/10.1093/nar/gkq294
- ↑ Aoki K, Adachi S, Homoto M, Kusano H, Koike K, Natsume T. LARP1 specifically recognizes the 3' terminus of poly(A) mRNA. FEBS Lett. 2013 Jul 11;587(14):2173-8. doi: 10.1016/j.febslet.2013.05.035. Epub, 2013 May 24. PMID:23711370 doi:http://dx.doi.org/10.1016/j.febslet.2013.05.035
- ↑ Tcherkezian J, Cargnello M, Romeo Y, Huttlin EL, Lavoie G, Gygi SP, Roux PP. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation. Genes Dev. 2014 Feb 15;28(4):357-71. doi: 10.1101/gad.231407.113. PMID:24532714 doi:http://dx.doi.org/10.1101/gad.231407.113
- ↑ Kozlov G, Mattijssen S, Jiang J, Nyandwi S, Sprules T, Iben JR, Coon SL, Gaidamakov S, Noronha AM, Wilds CJ, Maraia RJ, Gehring K. Structural basis of 3'-end poly(A) RNA recognition by LARP1. Nucleic Acids Res. 2022 Aug 18. pii: 6671114. doi: 10.1093/nar/gkac696. PMID:35979957 doi:http://dx.doi.org/10.1093/nar/gkac696
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