GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase

Nat Struct Mol Biol. 2019 Jul;26(7):628-636. doi: 10.1038/s41594-019-0249-3. Epub 2019 Jun 17.


Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and 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 carboxy-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'.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / chemistry
  • Alkyl and Aryl Transferases / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Dimethylallyltranstransferase / chemistry
  • Dimethylallyltranstransferase / metabolism*
  • F-Box Proteins / chemistry
  • F-Box Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Polyubiquitin / metabolism
  • Protein Conformation
  • Protein Prenylation
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism


  • F-Box Proteins
  • FBXL2 protein, human
  • Protein Subunits
  • Polyubiquitin
  • Alkyl and Aryl Transferases
  • RABGGTB protein, human
  • Dimethylallyltranstransferase
  • PTAR1 protein, human