Conserved and divergent features of the structure and function of La and La-related proteins (LARPs)

Abstract

Genuine La proteins contain two RNA binding motifs, a La motif (LAM) followed by a RNA recognition motif (RRM), arranged in a unique way to bind RNA. These proteins interact with an extensive variety of cellular RNAs and exhibit activities in two broad categories: i) to promote the metabolism of nascent pol III transcripts, including precursor-tRNAs, by binding to their common, UUU-3'OH containing ends, and ii) to modulate the translation of certain mRNAs involving an unknown binding mechanism. Characterization of several La-RNA crystal structures as well as biochemical studies reveal insight into their unique two-motif domain architecture and how the LAM recognizes UUU-3'OH while the RRM binds other parts of a pre-tRNA. Recent studies of members of distinct families of conserved La-related proteins (LARPs) indicate that some of these harbor activity related to genuine La proteins, suggesting that their UUU-3'OH binding mode has been appropriated for the assembly and regulation of a specific snRNP (e.g., 7SK snRNA assembly by hLARP7/PIP7S). Analyses of other LARP family members (i.e., hLARP4, hLARP6) suggest more diverged RNA binding modes and specialization for cytoplasmic mRNA-related functions. Thus it appears that while genuine La proteins exhibit broad general involvement in both snRNA-related and mRNA-related functions, different LARP families may have evolved specialized activities in either snRNA or mRNA related functions. In this review, we summarize recent progress that has led to greater understanding of the structure and function of La proteins and their roles in tRNA processing and RNP assembly dynamics, as well as progress on the different LARPs.La exhibits general and broad activity in both snRNA and mRNA-related functions La proteins are factors found in nearly all eukaryotes examined [1] and have important functions in RNA metabolism. Human La (hLa, also called Sjogren's Syndrome Antigen B, or SS-B) was first identified as an autoantigen in patients suffering from autoimmune disorders such as systemic lupus erythematosus, Sjogren's syndrome and neonatal lupus [2,3]. Although it remains unclear why La is targeted as an autoantigen in some persons, its

Overexpression of a LAM Domain Containing RNA-Binding Protein LARPIc Induces Precocious Leaf Senescence in Arabidopsis

“…La-related proteins (LARPs), which contain a conserved La motif (LAM) domain and are normally immediately followed by a canonical RNA recognition motif (RRM) or noncanonical RRMlike (RRM-L) motif, are widely present in eukaryotes (Bayfield et al, 2010;Bousquet-Antonelli and Deragon, 2009). The co-evolving LAM-RRM/RRM-L regions are suggested to cooperate functionally for RNA (e.g., SnRNA and mRNA) binding activity (Bousquet-Antonelli and Deragon, 2009).…”

“…Bioinformatic analyses of the LAM region showed that the Arabidopsis genome harbors six LARP genes (LARP1a-1c and LARP6a-6c) (Bayfield et al, 2010;Bousquet-Antonelli and Deragon, 2009), but their biological functions have not been studied previously. Here, we report that overexpression of LARP1c led to premature leaf senescence.…”

An intrinsically disordered C terminus allows the La protein to assist the biogenesis of diverse noncoding RNA precursors

“…Although La is dispensable for growth in budding and fission yeast, La becomes essential in the presence of mutations that compromise the structure of essential pre-tRNAs or impair snRNP assembly (4,5). While many of the mutations cause the affected RNA to be degraded without La, Saccharomyces cerevisiae La is required for correct folding of pre-tRNA Arg CCG when the tRNA carries a mutation that weakens the anticodon stem, allowing formation of an incorrect helix.…”

“…La binds the UUU OH that is the initial end of all RNA polymerase III transcripts and protects the RNAs from exonucleases (4,5). In budding yeast, La also binds processing intermediates of RNA polymerase II-transcribed small nuclear and nucleolar RNAs that end in UUU OH (6)(7)(8).…”

“…La contains an N-terminal La domain that adopts a winged helix-turn-helix fold, one or two RNA recognition motifs (RRMs), and a disordered C terminus (13-15). As the UUU OH binds in a cleft between the La and RRM domains (16, 17), but does not involve the canonical nucleic acid-binding surfaces of either the winged helix or the RRM, it is proposed that these surfaces assist folding (5,17,18). However, this model is difficult to reconcile with the finding that binding of the S. cerevisiae La to a pre-tRNA reduces the accessibility of the anticodon stemloop to chemical and enzymatic probes (11), because neither the La domain nor the RRM is sufficient to span the ∼70 Å between the 3′ end and the anticodon loop.…”