GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase
Authors: Antonio Marzio
Mark R Philips
Nicole Fehrenbacher
Ning Zheng
Kunj Jain
Harrison Homer
Michele Pagano
Shafi Kuchay
Hui Wang
Journal: Nature Structural & Molecular Biology (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Protein prenylation; Prenyltransferase complex; GGTase3; FBXL2; Membrane localization
Affiliations: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA., Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA., Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY, USA., Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA., Department of Pharmacology, University of Washington, Seattle, WA, USA., Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA., Department of Pharmacology, University of Washington, Seattle, WA, USA. ., Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. ., Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA. ., Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA. ., Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY, USA. .

Abstract:  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'. 

Retracted: No

PubPeer comments:
 The study is already at Pubpeer [[1] , [2] ] while there are again issues here with basic numbers. ![file] , 
 #1 Thank you for your comment and pointing this out. We would like to clarify that participants included in this analysis were not required to complete all the previous follow-up examinations. The inclusion criterion was only that they participated u201cat leastu201d in the 20-year follow-up or 15-year follow-up, respectively. Hence, the participants in the 20-year analysis are not necessarily a complete subset of the 15-year follow-up and it is possible, that some subjects did not complete the 15-year follow-up but the 20-year follow-up. The same applies to the analysis of the 15-year data in comparison to previous follow-ups until the age of 10 years. We hope this makes it clearer. ,