GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase.

Abstract

Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1, GGTase2. Here, we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase α subunit, PTAR1, and the catalytic β subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical C-terminal CaaX prenylation-motif that is predicted to be recognized by GGtase1. Our crystal structure analysis of the full-length GGTase3-FBXL2-SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the “prenylation code”.