InterPro domain: IPR014886

This entry represents the atypical RRM, named xRRM, found in La and La-related proteins (LaRPs). They belong to an ancient superfamily of proteins that are conserved in nearly all eukaryotes, except Plasmodium. These proteins are broadly involved in critical processes of RNA use and metabolism in the nucleus and the cytoplasm. The LaRP superfamily is distinguished by a conserved bipartite RNA-binding unit called the La-module, composed by a Lupus antigen motif (LaM) followed by an RNA-Recognition motif (RRM). Beyond this, each LaRP family is characterized by distinct family specific domains and motifs that contribute to structure and function. Genuine La and La-related proteins group 7 (LARP7) bind to the non-coding RNAs transcribed by RNA polymerase III (RNAPIII), which end in UUU. The La-module of these proteins bind the UUU-3'OH, protecting the RNA from degradation, while other domains may be important for RNA folding or others functions. The La and LaRP7 protein families have a C-terminal domain that contains a novel class of atypical RRM, named xRRM (for atypical RRM with extended alpha3), which uses a unique mode of single- and double-strand RNA binding [ 1 , 2 , 3 , 4 , 5 ].

The overall fold of the xRRM is an RRM, but with several atypical features. Unusual features of the xRRM include the absence of conserved RNP1 and RNP2 aromatic sequences on the beta3 and beta1 strands, respectively, typically involved in nucleotide recognition; the presence of an additional helix alpha3 that lies across the beta-sheet surface, where single-stranded nucleotides usually bind; and a C-terminal tail required for RNA binding that is disordered in the free xRRM but forms an alpha3 extension (alpha3x) on binding RNA. The front face of the xRRM consists of an antiparallel beta-sheet with helix alpha3 lying across the beta-sheet perpendicular to the beta-strand axis. The back side of the xRRM consists of alpha helices. The xRRM interacts with both single- and double-stranded RNA using the beta-sheet surface and the C-terminal tail, which forms a helical extension of alpha3 (alhpa3x) that binds to the RNA major groove[ 6 , 6 , 6 , 6 , 6 ].

1. Structure of the C-terminal domain of human La protein reveals a novel RNA recognition motif coupled to a helical nuclear retention element. Structure 11, 833-43
2. Structural basis for telomerase RNA recognition and RNP assembly by the holoenzyme La family protein p65. Mol. Cell 47, 16-26
3. xRRM: a new class of RRM found in the telomerase La family protein p65. RNA Biol 10, 353-9
4. hLARP7 C-terminal domain contains an xRRM that binds the 3' hairpin of 7SK RNA. Nucleic Acids Res 44, 9977-9989
5. The La-related proteins: structures and interactions of a versatile superfamily of RNA-binding proteins. RNA Biol 18, 178-193