The association of a La module with the PABP-interacting motif PAM2 is a recurrent evolutionary process that led to the neofunctionalization of La-related proteins

Abstract

La-related proteins (LARPs) are largely uncharacterized factors, well conserved throughout evolution. Recent reports on the function of human LARP4 and LARP6 suggest that these proteins fulfill key functions in mRNA metabolism and/or translation. We report here a detailed evolutionary history of the LARP4 and 6 families in eukaryotes. Genes coding for LARP4 and 6 were duplicated in the common ancestor of the vertebrate lineage, but one LARP6 gene was subsequently lost in the common ancestor of the eutherian lineage. The LARP6 gene was also independently duplicated several times in the vascular plant lineage. We observed that vertebrate LARP4 and plant LARP6 duplication events were correlated with the acquisition of a PABPinteracting motif 2 (PAM2) and with a significant reorganization of their RNA-binding modules. Using isothermal titration calorimetry (ITC) and immunoprecipitation methods, we show that the two plant PAM2-containing LARP6s (LARP6b and c) can, indeed, interact with the major plant poly(A)-binding protein (PAB2), while the third plant LARP6 (LARP6a) is unable to do so. We also analyzed the RNA-binding properties and the subcellular localizations of the two types of plant LARP6 proteins and found that they display nonredundant characteristics. As a whole, our results support a model in which the acquisition by LARP4 and LARP6 of a PAM2 allowed their targeting to mRNA 39 UTRs and led to their neofunctionalization.

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)

“…PABP-interacting protein 1 and 2 (PAIP1 and PAIP2) and eukaryotic release factor 3 (eRF3)) associate with PABP via classical PAM2 motifs (68). LARP4, another member of the LARP family of proteins, has been previously shown to associate with PABP via a noncanonical PAM2 motif that comprises a tryptophan in place of the critical phenylalanine typically found in classical PAM2 motifs (69,70). Thus, we investigated whether LARP1 also possessed a PAM2 motif.…”

Conservation of RNA chaperone activity of the human La-related proteins 4, 6 and 7

“…The LARP4 and LARP6 families are not as well understood, and recent computational analyses indicate that some members of these have acquired the capacity to engage cytoplasmic poly-A binding protein via the acquisition of a PAM2 (or variant PAM2) motif; these same family members (but not ones lacking the PAM2 motif) also show decreased homology in LAM amino acids associated with UUU-3′OH-dependent RNA binding (33). Thus, human LARP6 (hLARP6) lacks such a PAM2 motif and contains 100% conservation with hLa LAM amino acids associated with terminal uridylate binding, despite the only known RNA target of this protein being an internal stem loop in the 5′UTRs of the α1 and α2 collagen mRNAs (34).…”

The role of LARP1 in translation and beyond

“…AtLARP1 was found to act as a cofactor of the heat induced mRNA degradation process. It putatively forms a direct interaction with XRN4 in response to heat and acts at least, to target XRN4 to the polyribosomes where a subset of transcripts were found to be decapped and co‐translationally 5′‐digested (Refs ) (Figure ). Hence under heat stress, AtLARP1 appears to have a destabilizing effect on its mRNA targets.…”