Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Sep;9(5):e1480.
doi: 10.1002/wrna.1480. Epub 2018 May 2.

LARP1 on TOP of ribosome production

Bruno D Fonseca  1 , Roni M Lahr  2 , Christian K Damgaard  3 , Tommy Alain  1 , Andrea J Berman  2
Affiliations
Review

LARP1 on TOP of ribosome production

Bruno D Fonseca et al. Wiley Interdiscip Rev RNA. 2018 Sep.

Abstract

The ribosome is an essential unit of all living organisms that commands protein synthesis, ultimately fuelling cell growth (accumulation of cell mass) and cell proliferation (increase in cell number). The eukaryotic ribosome consists of 4 ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs). Despite its fundamental role in every living organism, our present understanding of how higher eukaryotes produce the various ribosome components is incomplete. Uncovering the mechanisms utilized by human cells to generate functional ribosomes will likely have far-reaching implications in human disease. Recent biochemical and structural studies revealed La-related protein 1 (LARP1) as a key new player in RP production. LARP1 is an RNA-binding protein that belongs to the LARP superfamily; it controls the translation and stability of the mRNAs that encode RPs and translation factors, which are characterized by a 5' terminal oligopyrimidine (5'TOP) motif and are thus known as TOP mRNAs. The activity of LARP1 is regulated by the mammalian target of rapamycin complex 1 (mTORC1): a eukaryotic protein kinase complex that integrates nutrient sensing with mRNA translation, particularly that of TOP mRNAs. In this review, we provide an overview of the role of LARP1 in the control of ribosome production in multicellular eukaryotes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Capping and 5' End Modifications.

Keywords: 5′TOP; LARP1; La-related protein; RNA-binding protein; TIA; TIAR; TOP mRNA; mRNA cap; mTORC1; terminal oligopyrimidine; translation regulation.

PubMed Disclaimer

Conflict of interest statement

These authors declare no conflict of interest.

Figures

Figure 1
Figure 1. LARP superfamily Homo sapiens (Hs) and Saccharomyces cerevisiae (Sc) evolutionary tree
Abbreviations: LaM, La motif; LARP1, La-related protein 1; LARP2/1b, La-related protein 2/1b; La, lupus autoantigen; LARP4/4a, La-related protein 4/4a; LARP5/4b, La-related protein 5/4b; LARP6, La-related protein 6; LARP7, La-related protein 7; RRM, RNA-recognition motif; RRM-L4, RNA recognition motif-like 4; RRM-L5, RNA recognition motif-like 5; PBM, PABP binding motif; PAM2, PABP interaction motif 2; LSA, LaM and S1 associated motif; 5′TOP, 5′terminal oligopyrimidine; SBM, short basic motif; sn7SK RNA, small nuclear 7SK RNA; SL, stem loop.
Figure 2
Figure 2. Crystal packing revealed a G-binding pocket 5′ of the +1C binding pocket in the LARP1 DM15 region
Crystals are comprised of molecules packed into unit cells that relate to each other by symmetry operations; three unit cells are shown (PDBID 5V7C). The red DM15 molecule (cartoon representation) binds nucleotides C1–U5 of the yellow oligonucleotide (stick representation). Nucleotide G8 from the RNA bound to the neighboring molecule of DM15 (RNA, C1–C7 shown as a black line connected to G8 shown as sticks; DM15, grey cylinders) binds the red DM15 molecule upstream of the +1C of the yellow oligonucleotide.
Figure 3
Figure 3. Conservation of cap-binding architecture in LARP1
A. m7GpppC bound to the DM15 region of LARP1 (PDBID 5V87). B. m7GpppG bound to eIF4E (PDBID 3HXI).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aloni R, Peleg D, Meyuhas O. Selective translational control and nonspecific posttranscriptional regulation of ribosomal protein gene expression during development and regeneration of rat liver. Mol Cell Biol. 1992;12:2203–2212. - PMC - PubMed
    1. Altmann M, Schmitz N, Berset C, Trachsel H. A novel inhibitor of cap-dependent translation initiation in yeast: p20 competes with eIF4G for binding to eIF4E. EMBO J. 1997;16:1114–1121. - PMC - PubMed
    1. 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;587:2173–2178. - PubMed
    1. Aronica SM, Gingras AC, Sonenberg N, Cooper S, Hague N, Broxmeyer HE. Macrophage inflammatory protein-1alpha and interferon-inducible protein 10 inhibit synergistically induced growth factor stimulation of MAP kinase activity and suppress phosphorylation of eukaryotic initiation factor 4E and 4E binding protein 1. Blood. 1997;89:3582–3595. - PubMed
    1. Avni D, Biberman Y, Meyuhas O. The 5′ terminal oligopyrimidine tract confers translational control on TOP mRNAs in a cell type- and sequence context-dependent manner. Nucleic Acids Res. 1997;25:995–1001. - PMC - PubMed

Further Reading

    1. Lahr RM, Fonseca BD, Ciotti GE, Al-Ashtal HA, Jia JJ, Niklaus MR, Blagden SP, Alain T, Berman AJ. La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs. eLife. 2017:6. - PMC - PubMed
    1. Fonseca BD, Zakaria C, Jia JJ, Graber TE, Svitkin Y, Tahmasebi S, Healy D, Hoang HD, Jensen JM, Diao IT, Lussier A, Dajadian C, Padmanabhan N, Wang W, Matta-Camacho E, Hearnden J, Smith EM, Tsukumo Y, Yanagiya A, Morita M, Petroulakis E, Gonzalez JL, Hernandez G, Alain T, Damgaard CK. La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1) The Journal of Biological Chemistry. 2015;290:15996–16020. - PMC - PubMed
    1. Meyuhas O, Kahan T. The race to decipher the top secrets of TOP mRNAs. Biochimica et Biophysica Acta. 2015;1849:801–81. - PubMed
    1. Fonseca BD, Smith EM, Yelle N, Alain T, Bushell M, Pause A. The ever-evolving role of mTOR in translation. Seminars in Cell & Developmental Biology 2014 - PubMed
    1. Damgaard CK, Lykke-Andersen J. Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR. Genes & Development. 2011;25:2057–2068. - PMC - PubMed