General
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Guanylate-binding protein 1 (GBP1) is farnesylated at cysteine 589 (C589) (Nantais et al., 1996; Fres JM et al., 2010; Fisch et al., 2019; Shydlovskyi et al., 2017). Farnesylation is a type of prenylation in which a 15-carbon farnesyl (FARN) isoprenoid group, donated by farnesyl diphosphate (FPP), is covalently attached to a cysteine residue on a protein. This reaction is catalyzed by the enzyme farnesyltransferase (FNT), a heterodimer composed of an alpha subunit, FNTA (shared with another prenylating enzyme, geranylgeranyltransferase or GGTase), and a unique beta subunit, FNTB (Long SB et al., 2001; deSolms et al., 2003). The FNTA:FNTB complex recognizes the CAAX box motif at the C-terminus of target proteins, where C = cysteine, A = any aliphatic amino acid, and X = any amino acid. In the case of GBP1, the CAAX motif is CTIS. In the absence of nucleotides, the farnesyl group of GBP1 is sequestered in a hydrophobic pocket, maintaining the protein in an inactive, monomeric conformation (Lorenz et al., 2020; Sistemich et al., 2020). Upon GTP binding, farnesylated GBP1 undergoes a nucleotide-dependent "farnesyl switch," which releases the farnesyl tail from the hydrophobic pocket, enabling membrane binding and polymerization into large structures (Sistemich et al., 2020; Kuhm et al., 2025). Farnesylated GBP1 localizes to the microbial membranes (reviewed by Tretina K et al., 2019). For instance, GBP1 localizes to the lipopolysaccharide (LPS)-rich outer membranes of cytosolic Gram-negative bacteria, where it oligomerizes and facilitates the assembly of a caspase-4–activating platform (Santos et al., 2020; Wandel et al., 2020; Dickinson et al., 2023).
