Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities

Abstract

Summary Protein lipidation is an important co- or post-translational modification in which lipid moieties are covalently attached to proteins. Lipidation markedly increases the hydrophobicity of proteins, resulting in changes to their conformation, stability, membrane association, localization, trafficking, and binding affinity to their co-factors. Various lipids and lipid metabolites serve as protein lipidation moieties. The intracellular concentrations of these lipids and their derivatives are tightly regulated by cellular metabolism. Therefore, protein lipidation links the output of cellular metabolism to the regulation of protein function. Importantly, deregulation of protein lipidation has been linked to various diseases, including neurological disorders, metabolic diseases and cancers. In this review, we highlight recent progress in our understanding of protein lipidation, in particular, S-palmitoylation and lysine fatty acylation, and we describe the importance of these modifications for protein regulation, cell signaling and diseases. We further highlight opportunities and new strategies for targeting protein lipidation for therapeutic applications.

Protein palmitoylation and cancer

“…Lipidated proteins generally have greater affinity for non‐polar structures such as lipid bilayers, with important consequences for the localization, diffusion, and physical interactions of these proteins within the cell. Indeed, lipidation of key signaling proteins, such as Hedgehog, Wnt, and RAS, is essential for their function, both normally and in cancer .…”

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

“…Hence, aberrant activation of the Wnt-FZD signaling leads to tumorigenesis in many tissues [123], including the breast [124], prostate [125], colon, brain [126], and pancreas [127,128]. In this context, Wnt proteins are modified by lipidation, a post-translational addition essential for their activity in both normal and cancer cells [129]. Members of the Wnt family undergo two types of post-translational modification that influence their interactions with lipid bilayers and that are essential for Wnt signaling: serine acylation and the subsequent S-palmitoylation of cysteine.…”

Synthetic Strategies for Artificial Lipidation of Functional Proteins

“…For example, two major fatty acid groups, C14 myristoyl (C14) and C16 palmitoyl (C16), are differentially attached onto target proteins in eukaryotic cells. Although the C16 group is more abundant in a cellular environment, the less hydrophobic C14 tail is used for specific lipidation of a Src kinase family protein such as c‐Src to assist its membrane binding, stability, and activity. The titrated interaction between the C14 group and the membrane surface compared with that of the C16 chain is assumed to be related to the extent of activation of proliferation and oncogenesis of the lipidated form.…”