7sow | pdb_00007sow
LaM domain of human LARP1 in complex with UUUUUU
Structural highlights
FunctionLARP1_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 PubMedLa-related proteins (LARPs) are a family of RNA-binding proteins that share a conserved La motif (LaM) domain. LARP1 plays a role in regulating ribosomal protein synthesis and stabilizing mRNAs and has a unique structure without an RNA binding RRM domain adjoining the LaM domain. In this study, we investigated the physical basis for LARP1 specificity for poly(A) sequences and observed an unexpected bias for sequences with single guanines. Multiple guanine substitutions did not increase the affinity, demonstrating preferential recognition of singly guanylated sequences. We also observed that the cyclic di-nucleotides in the cCAS/STING pathway, cyclic-di-GMP and 3',3'-cGAMP, bound with sub-micromolar affinity. Isothermal titration measurements were complemented by high-resolution crystal structures of the LARP1 LaM with six different RNA ligands, including two stereoisomers of a phosphorothioate linkage. The selectivity for singly substituted poly(A) sequences suggests LARP1 may play a role in the stabilizing effect of poly(A) tail guanylation. [Figure: see text]. Enhanced binding of guanylated poly(A) RNA by the LaM domain of LARP1.,Kozlov G, Jiang J, Rutherford T, Noronha AM, Wilds CJ, Gehring K RNA Biol. 2024 Jan;21(1):7-16. doi: 10.1080/15476286.2024.2379121. Epub 2024 Jul , 17. PMID:39016322[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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