Taking a Step Back from Back-Translocation: an Integrative View of LepA/EF4's Cellular Function

Protein synthesis, the translation of mRNA into a polypeptide facilitated by the ribosome, is assisted by a variety of protein factors, some of which are GTPases. In addition to four highly conserved and well-understood GTPases with known function, there are also a number of noncanonical GTPases that are implicated in translation but whose functions are not fully understood. LepA/EF4 is one of these noncanonical GTPases. It is highly conserved and present in bacteria, mitochondria, and chloroplasts, but its functional role in the cell remains unknown. LepA's sequence and domain arrangement are very similar to those of other translational GTPases, but it contains a unique C-terminal domain (CTD) that is likely essential to its specific function in the cell. Three main hypotheses about the function of LepA have been brought forward to date: (i) LepA is a back-translocase, (ii) LepA relieves ribosome stalling or facilitates sequestration, and (iii) LepA is involved in ribosome biogenesis. This review examines the structural and biochemical information available on bacterial LepA and discusses it on the background of the available in vivo information from higher organisms in order to broaden the view regarding LepA's functional role in the cell and how the structure of its unique CTD might be involved in facilitating this role.