Abstract
Poly(A)-binding protein (PABPC1) is involved in multiple aspects of mRNA processing and translation. It is a component of RNA stress granules and binds the RNA-induced silencing complex to promote degradation of silenced mRNAs. Here, we report the crystal structures of the C-terminal Mlle (or PABC) domain in complex with peptides from GW182 (TNRC6C) and Ataxin-2. The structures reveal overlapping binding sites but with unexpected diversity in the peptide conformation and residues involved in binding. The mutagenesis and binding studies show low to submicromolar binding affinity with overlapping but distinct specificity determinants. These results rationalize the role of the Mlle domain of PABPC1 in microRNA-mediated mRNA deadenylation and suggest a more general function in the assembly of cytoplasmic RNA granules.
Highlights
Poly(A)-binding protein (PABP) homolog RRM4 in filamentous fungi (4, 5)
Structure of the GW182-Mlle Complex—To understand the molecular basis of GW182 recognition by the Mlle domain of PABPC1, we co-crystallized Mlle with a peptide from the DUF region of GW182 (17). This region had previously been recognized as similar to the PABPC1-binding PAM2 motif, and PAM2 peptides derived from Paip2 were shown to block the pulldown of PABPC1 by GW182 (11)
The crystal structure was solved by molecular replacement to 1.5 Å and showed the presence of the Mlle domain (PABPC1 residues 544 – 626) in complex with a 22-residue fragment of GW182
Summary
The Mlle domain binds proteins that contain a 12–15-amino acid motif, termed PAM2 (1). Most proteins that contain PAM2 motifs appear to bind to the Mlle domain of PABPC1. We report the crystal structures of the Mlle domain of PABPC1 with peptides from GW182 and Ataxin-2.
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