Abstract
The La-related proteins (LARPs) form a diverse group of RNA-binding proteins characterized by the possession of a composite RNA binding unit, the La module. The La module comprises two domains, the La motif (LaM) and the RRM1, which together recognize and bind to a wide array of RNA substrates. Structural information regarding the La module is at present restricted to the prototypic La protein, which acts as an RNA chaperone binding to 3′ UUUOH sequences of nascent RNA polymerase III transcripts. In contrast, LARP6 is implicated in the regulation of collagen synthesis and interacts with a specific stem-loop within the 5′ UTR of the collagen mRNA. Here, we present the structure of the LaM and RRM1 of human LARP6 uncovering in both cases considerable structural variation in comparison to the equivalent domains in La and revealing an unprecedented fold for the RRM1. A mutagenic study guided by the structures revealed that RNA recognition requires synergy between the LaM and RRM1 as well as the participation of the interdomain linker, probably in realizing tandem domain configurations and dynamics required for substrate selectivity. Our study highlights a considerable complexity and plasticity in the architecture of the La module within LARPs.
Highlights
The La-related proteins (LARPs) form a large and diverse superfamily of over 250 eukaryotic RNA-binding proteins that has emerged from recent phylogenetic analyses (1) and is divided into five distinct protein families: LARP1, La, LARP4, LARP6 and LARP7 (Figure 1)
In this paper we report a detailed investigation on the structure and RNA interactions of human LARP6
The high resolution structure determination of HsLARP6 RRM1 exposed an as yet unseen RRM-based fold, featuring an unprecedented version of loop 3, in that it contains an ␣-helix firmly seated on the canonical -sheet face, probably precluding it from serving as the main RNA recognition platform of the domain
Summary
The La-related proteins (LARPs) form a large and diverse superfamily of over 250 eukaryotic RNA-binding proteins that has emerged from recent phylogenetic analyses (1) and is divided into five distinct protein families: LARP1, La (aka LARP3), LARP4, LARP6 and LARP7 (Figure 1). LARPs perform a variety of discrete cellular functions (2), they share a conserved two-domain RNA binding unit, termed the ‘La module’, first identified in the La protein (3,4) and composed of a La motif (LaM), a novel type of winged-helix domain, and an RNA recognition motif (RRM1) (Figure 1). The recognition of uridylatecontaining 3 ends by human La is achieved by a synergic interplay of the LaM and RRM1 whereby the two domains adopt an induced configuration around the RNA tailored for high-specificity binding to 3 oligoU targets.
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