Release factors eRF1 and RF2: A universal mechanism controls the large conformational changes

Buyong Ma, Ruth Nussinov

Research output: Contribution to journalArticlepeer-review

Abstract

Class I release factors 1 and 2 (EF1 and RF2) terminate protein synthesis by recognizing stop codons on the mRNA via their conserved amino acid motifs (NIKS in eRF1 and SPF in RF2) and by the conserved tripeptide (GGQ) interactions with the ribosomal peptidyltransferase center. Crystal structures of eRF1 and RF2 do not fit their ribosomal binding pocket (∼73 Å). Cryoelectron microscopy indicates large conformational changes in the ribosome-bound RF2. Here, we investigate the conformational dynamics of the eRF1 and RF2 using molecular dynamics simulation, structural alignment, and electrostatic analysis of domain interactions. We show that relaxed eRF1 has a shape remarkably similar to the ribosome-bound RF2 observed by cryoelectron microscopy. The similarity between the two release factors is as good as between elongation factor G and elongation factor Tuguanosine-5†(β,γ-imido)triphospliate-tRNA. Further, the conformational transitions and dynamics of eRF1 and RF2 between the free and ribosome-bound states are most likely controlled by protonation of conserved histidines. For eRF1, the distance between the NIKS and GGQ motifs shrinks from 97.5 A in the crystal to 70-80 Å. For RF2, the separation between SPF and GGQ elongates from 32 Å in the crystal to 50 Å. Coulombic interaction strongly favors the open conformation of eRF1; however, solvation and histidine protonation modulate the domain interactions, making the closed conformation of eRF1 more accessible. Thus, RF1 and RF2 function like molecular machines, most likely fueled by histidine protonation. The unified conformational control and the shapes of eRF1 and RF2 support the proposition that the termination of protein synthesis involves similar mechanisms across species.

Original languageEnglish
Pages (from-to)53875-53885
Number of pages11
JournalJournal of Biological Chemistry
Volume279
Issue number51
DOIs
StatePublished - 17 Dec 2004

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