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Abstract The synthesis of ribosomes in metazoans is an essential process that is dysregulated in disease. Previous studies implicate La-related protein 1 (LARP1) in binding inactive ribosomes and in repressing Terminal OligoPyrimidine motif mRNAs (TOPs), which encode ribosomal proteins. While the molecular details of LARP1 binding to the ribosome and to TOP mRNAs are deciphered, the mechanistic link between these two activities is not understood. Here, we show that ribosome binding is an essential step in LARP1-mediated TOP repression. LARP1’s ribosome binding region is part of a previously unrecognized RNA recognition motif (RRM) domain, which in turn directly interacts with its TOP-binding HEAT repeat domain. Remarkably, ribosome binding is both sufficient in vitro and required in cells for LARP1 to bind, repress, and stabilize TOPs via unfolding and remodeling of the RRM domain. Disrupting the coordinated architecture of these domains by mutating the RRM constitutively represses TOPs and compromises cell fitness. Together, these data reveal a general ribosome-sensing function of LARP1, orchestrated through the unique coordinating role of its RRM, which tunes the synthesis of ribosomal proteins to cellular demand for ribosomes.
Saba et al. (Sun,) studied this question.