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Protein prenylation: unique fats make their mark on biology

Nature Reviews Molecular Cell Biology volume 17, pages 110–122 (2016)Cite this article

Subjects

Key Points

  • A large repertoire of eukaryotic proteins, termed prenylated proteins, are subject to post-translational modification by isoprenoid lipids.

  • The attached lipid can markedly affect the cellular location of the prenylated protein, as well as its function.

  • Prenylated proteins have been implicated in diseases ranging from cancer to inflammation and premature ageing.

  • The enzymes that catalyse the reactions leading to a mature prenylated protein are under investigation as drug targets in various diseases.

Abstract

The modification of eukaryotic proteins by isoprenoid lipids, which is known as prenylation, controls the localization and activity of a range of proteins that have crucial functions in biological regulation. The roles of prenylated proteins in cells are well conserved across species, underscoring the biological and evolutionary importance of this lipid modification pathway. Genetic suppression and pharmacological inhibition of the protein prenylation machinery have provided insights into several cellular processes and into the aetiology of diseases in which prenylation is involved. The functional dependence of prenylation substrates, such as RAS proteins, on this modification and the therapeutic potential of targeting the prenylation process in pathological conditions accentuate the need to fully understand this form of post-translational modification.

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Figure 1: Isoprenoid metabolism and CAAX protein prenylation.
Figure 2: Roles of protein-associated isoprenoids in protein–protein interactions and membrane targeting.
Figure 3: Completion of prelamin A maturation into lamin A depends on three-step prenylation processing.<ct:Light Italic>

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Acknowledgements

The authors thank the reviewers for helpful comments on the manuscript and express regret that they could not reference all of the important studies that have contributed to the understanding of protein prenylation. They also thank Zheng Huan Tay for his assistance with the figures. Work from the authors' laboratories is funded by the Ministries of Health and Education of Singapore.

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  1. Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore

    Mei Wang & Patrick J. Casey

  2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Patrick J. Casey

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Glossary

CAAX proteins

Proteins containing a CAAX motif at their carboxyl termini, in which 'C' is the Cys residue that functions as the isoprenoid attachment site, 'A' signifies any aliphatic amino acid, and 'X' denotes any of several amino acids.

HMG-CoA reductase

(HMGCR). The rate-controlling enzyme of the mevalonate pathway of cholesterol and isoprenoid biosynthesis and the target of the widely-used statin drugs.

Sterols

The major biosynthetic end products of the isoprenoid biosynthetic pathway; sterols occur naturally in eukaryotic organisms, with the most well-recognized animal sterol being cholesterol.

Mevalonate

The direct product of the HMG-CoA reductase (HMGCR) reaction and the first committed intermediate in the biosynthetic pathway that produces isoprenoids and, subsequently, sterols.

Prenylome

The repertoire of proteins in an organism that contain covalently attached isoprenoid lipids.

FTase inhibitors

(FTIs). Inhibitors of the protein farnesyltransferase (FTase) enzymes. FTIs have been used in clinical trials for the treatment of cancer, progeria and hepatitis D virus infection.

GDP/GTP exchange factors

(GEFs). Proteins that facilitate the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

Progeroid syndromes

A group of rare genetic disorders that result in markedly accelerated ageing.

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Wang, M., Casey, P. Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol 17, 110–122 (2016). https://doi.org/10.1038/nrm.2015.11

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