Identification of the GET pathway: a conserved system responsible for the biogenesis of tail-anchored membrane proteins

Tail-anchored (TA) proteins, defined by the presence of a single C-terminal transmembrane domain (TMD), play critical roles throughout the secretory pathway and in mitochondria. Because of its position near the C terminus, the TMD of TA proteins is occluded by the ribosome until translation is completed. Thus, TA proteins cannot exploit the classic cotranslational SRP/Sec61 translocation mechanism used by most secretory pathway proteins. Starting from our Genetic Interaction Map approach (see below), we identified the Guided Entry of Tail-anchor (GET) proteins as three components of a conserved machinery responsible for the biogenesis of TA proteins. Further genetic interactions maps identified two additional ribosome-associated components (Get4 and Get5). These and other observations suggest a pathway for the biogenesis of TA proteins in which Get4/5 recognize TA proteins as synthesis is completed. The TA is then delivered to a soluble ATPase, Get3, which is subsequently recruited to the ER membrane by a receptor composed of the Get1/2 proteins, thereby allowing proper membrane insertion.