La-Related Proteins and RNA Recognition

Robert Silvers^1,2

1. Department of Chemistry and Biochemistry, Florida State University
2. Institute of Molecular Biology, Florida State University

La-related proteins (LARPs) are a superfamily of RNA-binding proteins whose membership is dictated by the presence of a highly conserved domain called the La motif (LaM). In the vast majority of LARPs, LaM forms the La-module in tandem with a downstream ribonucleotide recognition motif (RRM). Human LARP1 (HsLARP1) is involved in post-transcriptional regulation of certain 5ʹ terminal oligopyrimidine (5ʹTOP) mRNAs as well as other mRNAs and several independent studies showed that HsLARP1 is heavily involved in cell proliferation, cell cycle defects, and cancer, where it is significantly upregulated in malignant cells and tissues. Human LARP6 (HsLARP6) is involved in post-transcriptional regulation of type I and III collagen biosynthesis. Unlike most LARPs, LARP6 recognizes a highly conserved, double-stranded RNA motif known as the 5’ stem loop (5’SL) found in the mRNAs coding for the type I and III collagen polypeptides. The 5’SL is between 46-48 nucleotides long and harbors 9 highly conserved nucleotides that form the internal loop which is flanked by two stems with higher sequence variability. The 5’SL motif is highly conserved across all vertebrates and plays a critical role in regulating the translation of these collagen mRNAs.

Here, we present the structural characterization of the LaM of HsLARP1 and HsLARP6 as well as the molecular basis for binding of HsLARP1 to the C-terminal domain of poly(A) binding protein (PABP) using solution NMR spectroscopy.