Abstract
Ricin is a type 2 ribosome-inactivating protein (RIP), containing a catalytic A chain and a lectin-like B chain. It inhibits protein synthesis by depurinating the N-glycosidic bond at α-sarcin/ricin loop (SRL) of the 28S rRNA, which thereby prevents the binding of elongation factors to the GTPase activation center of the ribosome. Here, we present the 1.6 Å crystal structure of Ricin A chain (RTA) complexed to the C-terminal peptide of the ribosomal stalk protein P2, which plays a crucial role in specific recognition of elongation factors and recruitment of eukaryote-specific RIPs to the ribosomes. Our structure reveals that the C-terminal GFGLFD motif of P2 peptide is inserted into a hydrophobic pocket of RTA, while the interaction assays demonstrate the structurally untraced SDDDM motif of P2 peptide contributes to the interaction with RTA. This interaction mode of RTA and P protein is in contrast to that with trichosanthin (TCS), Shiga-toxin (Stx) and the active form of maize RIP (MOD), implying the flexibility of the P2 peptide-RIP interaction, for the latter to gain access to ribosome.
Highlights
Ricin is a well-known type 2 ribosome-inactivating protein (RIP) discovered in the late 19th century in the seeds of Ricinus communis
A hydrophobic pocket at the C-terminal domain of RTA donates a major interface to associate with the hydrophobic GFGLFD motif on the human ribosomal stalk P2 peptide
We identified two arginines, R189, R193 probably interact with the N-terminal DDD motif of P2
Summary
Ricin is a well-known type 2 ribosome-inactivating protein (RIP) discovered in the late 19th century in the seeds of Ricinus communis. It agglutinates red blood cells and is one of the most potent and lethal substances known [1]. Ricin hydrolyzes the N-glycosidic bond at adenine−4324 in the 28S rRNA of eukaryotic ribosomes [2]. This adenine is located at a GAGA hairpin within the sarcin/ricin loop [3], which is highly conserved in all large ribosomal subunits and is essential for the proper assembly of the functional core of the large subunit [4]. Protein synthesis is arrested at the elongation step [5]
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