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

GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase.

Kuchay S1,2,3,4, Wang H5,6, Marzio A1,3, Jain K1,3, Homer H1,3, Fehrenbacher N1,3, Philips MR1,3, Zheng N7,8, Pagano M9,10,11.

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
2
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA.
3
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY, USA.
4
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.
5
Department of Pharmacology, University of Washington, Seattle, WA, USA.
6
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
7
Department of Pharmacology, University of Washington, Seattle, WA, USA. nzheng@uw.edu.
8
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. nzheng@uw.edu.
9
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA. michele.pagano@nyumc.org.
10
Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA. michele.pagano@nyumc.org.
11
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY, USA. michele.pagano@nyumc.org.

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'.

PMID:
31209342
PMCID:
PMC6609460
[Available on 2019-12-17]
DOI:
10.1038/s41594-019-0249-3

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