Editors' ChoicePosttranslational Modifications

Lipidating a ubiquitin ligase

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Science Signaling  02 Jul 2019:
Vol. 12, Issue 588, eaay5593
DOI: 10.1126/scisignal.aay5593

A previously undescribed enzyme promotes lipidation of a ubiquitin ligase that regulates PI3K and Ca2+ signaling.

The process of modifying target proteins with lipids, which is known as prenylation, is critically important for the correct subcellular localization of proteins involved in membrane trafficking and signaling. As critical as this modification is, only three heterodimeric enzyme complexes have defined roles in this process, and the precise molecular details of substrate selection remain unclear. Important for ubiquitylation and degradation of the p85β regulatory subunit of the kinase PI3K (phosphatidylinositol 3-kinase) and the inositol 1,4,5-trisphosphate receptor, the F-box protein FBXL2 contains a conserved, prototypic C-terminal prenylation motif and undergoes lipidation. In previous mass spectrometry studies, peptides corresponding to the orphan protein prenyltransferase α subunit repeat–containing protein 1 (PTAR1) and the Rab geranylgeranyltransferase subunit β (RabGGTB) copurified with FBXL2. Kuchay et al. validated that endogenous PTAR1 interacted with FBXL2 but not 14 other prenylation motif–containing proteins. Similarly, endogenous RabGGTB interacted with PTAR1 but not other prenyltransferase α subunits. In vitro, the purified PTAR1-RabGGTB complex, dubbed geranylgeranyltransferase type 3 (GGTase3), specifically promoted lipidation of FBXL2. In cells, knockdown of PTAR1 reduced the lipid modification of FBXL2 and promoted its mislocalization to the cytoplasm. Crystallography studies showed that GGTase3 has a unique N-terminal extension in PTAR1, which promoted its interaction with FBXL2. Mutation of residues in the N-terminal extension of PTAR1 or truncation of the C-terminal region of FBXL2 interfered with this interaction. Furthermore, these data identified molecular determinants outside of canonical prenylation motifs that are important for substrate selection. Not only does this study identify a previously uncharacterized enzyme involved in prenylation, but it also shows that ubiquitin ligases can undergo lipid modification to promote their membrane targeting. Additionally, this insight into how these enzymes select their substrates may help inform strategies to improve therapeutic targeting of other prenylated proteins, such as oncogenic Ras family GTPases.

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