The Peptidyl Transferase Center: a Window to the Past

In his 2001 article, "Translation: in retrospect and prospect," the late Carl Woese made a prescient observation that there was a need for the then-current view of translation to be "reformulated to become an all-embracing perspective about which 21st century Biology can develop" (RNA 7:1055-1067, 2001, https://doi.org/10.1017/s1355838201010615). The quest to decipher the origins of life and the road to the genetic code are both inextricably linked with the history of the ribosome. After over 60 years of research, significant progress in our understanding of how ribosomes work has been made. Particularly attractive is a model in which the ribosome may facilitate an ∼180° rotation of the CCA end of the tRNA from the A-site to the P-site while the acceptor stem of the tRNA would then undergo a translation from the A-site to the P-site. However, the central question of how the ribosome originated remains unresolved. Along the path from a primitive RNA world or an RNA-peptide world to a proto-ribosome world, the advent of the peptidyl transferase activity would have been a seminal event. This functionality is now housed within a local region of the large-subunit (LSU) rRNA, namely, the peptidyl transferase center (PTC). The PTC is responsible for peptide bond formation during protein synthesis and is usually considered to be the oldest part of the modern ribosome. What is frequently overlooked is that by examining the origins of the PTC itself, one is likely going back even further in time. In this regard, it has been proposed that the modern PTC originated from the association of two smaller RNAs that were once independent and now comprise a pseudosymmetric region in the modern PTC. Could such an association have survived? Recent studies have shown that the extant PTC is largely depleted of ribosomal protein interactions. It is other elements like metallic ion coordination and nonstandard base/base interactions that would have had to stabilize the association of RNAs. Here, we present a detailed review of the literature focused on the nature of the extant PTC and its proposed ancestor, the proto-ribosome.