LARP1 on TOP of ribosome production

Advanced Review

Bruno D. Fonseca, Roni M. Lahr, Christian K. Damgaard, Tommy Alain, Andrea J. Berman

Published Online: May 02 2018

DOI: 10.1002/wrna.1480

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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

LARP superfamily Homo sapiens (Hs) and Saccharomyces cerevisiae (Sc) evolutionary tree. 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

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Conservation of cap‐binding architecture in LARP1: (a) m⁷GpppC bound to the DM15 region of LARP1 (PDBID 5 V87) and (b) m⁷GpppG bound to eIF4E (PDBID 3HXI)

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Crystal packing revealed a G‐binding pocket 5′ of the +1C binding pocket of 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, gray cylinders) binds the red DM15 molecule upstream of the +1C of the yellow oligonucleotide

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