One of the essential post-translational modifications that proteins undergo is prenylation—the attachment of isoprenoids from farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), catalyzed by farnesyl and geranylgeranyl transferases (FTase and GGTase), respectively—which typically targets proteins to membranes for their proper function. Owing to the importance of this process in biological systems, a plethora of strategies have been extensively developed in targeting this pathway for therapeutic and biotechnological applications. Albeit canonical prenylation motifs have been determined experimentally and bioinformatically, there remains a dearth of experimental evidences to define the exact set of prenylated proteins (prenylome) across different systems. We conducted a chemical proteomic approach that employs metabolic labeling with an alkyne analogue of the isoprenoids (C15AlkOPP), which allowed for visualization and enrichment <i>via</i> click reaction with an azide-functionalized fluorophore or biotin, respectively. This approach enabled us to define the restricted set of prenylome in <i>Plasmodium falciparum</i>—the causal agent of malaria. Applying the same technique on virus-infected macrophages identified prenylated proteins that are known and potentially novel to be involved in controlling viral replication through interferon-signaling. Lastly, in vitro farnesylation in brain tissue homogenates from neuron-specific FTase knockout mice facilitated the profiling of neuronal prenylated proteins, including some with non-canonical prenylation motifs, which will be further investigated for their contribution to Alzheimer’s disease progression. Taken together, our work on identifying prenylated proteins and understanding their role in infection and disorder is of primary importance to provide new potential targets to diagnose and treat these diseases

Chemical proteomic profiling of prenylated proteins involved in disease

255th National Meeting (2018)

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