Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions

Abstract

Protein post-translational modifications increase the functional diversity of the proteome by covalently adding chemical moieties onto proteins thereby changing their activation state, cellular localization, interacting partners, and life cycle. Lipidation is one such modification that enables membrane association of naturally cytosolic proteins. Protein prenyltransferases irreversibly install isoprenoid units of varying length via a thioether linkage onto proteins that exert their cellular activity at membranes. Substrates of prenyltransferases are involved in countless signaling pathways and processes within the cell. Identification of new prenylation substrates, prenylation pathway regulators, and dynamic trafficking of prenylated proteins are all avenues of intense, ongoing research that are challenging, exciting, and have the potential to significantly advance the field in the near future.

Figure 1

The substrate selectivity of FTase for multiple turnover (MTO) and single turnover (STO) substrates. The region upstream of the CaaX sequence may contain a polybasic region (PBR). The selectivity at the a₂ and X positions is context-dependent.

Figure 2

Models for the trafficking and regulation of prenylated proteins. The farnesyl group is depicted here to represent prenylation. A) The prenylation of a Caax-containing protein is catalyzed by FTase or GGTase-I in the cytsosol. Next it is trafficked to the ER where it is proteoylzed by a CaaX protease such as Rce1 and carboxymethylated by isoprenylcysteine methyltransferase (ICMT). If the protein contains another cysteine near the C-terminus, a protein acyltransferase (PAT) can catalyze the palmitoylation of the protein at the Golgi. Then, the modified protein is trafficked to the plasma membrane. A protein acylthioesterase (APT) can catalyze the removal of the palmitoyl group, allowing for regulation of proteins between different cellular compartments. B) The SmgGDS-607 isoform and possibly a GEF-like protein may interact with an unmodified CaaX protein containing a polybasic region (PBR), promote GDP/GTP exchange, and allow the CaaX protein to enter the prenylation pathway. Once prenylated by GGTase-I or FTase, SmgGDS-558 may facilitate the release of the protein from the prenyltransferase and/or traffic the protein to the ER where it is subsequently proteolyzed and methylated. SmgGDS-558 may also transport the fully processed prenylated protein to and from the plasma membrane.

Figure 3

Bacteria hijack host prenylation machinery during infection. Upon bacterial entry via phagocytosis (1), the infectious bacterium is surrounded by a vacuole and immediately secretes effectors into the host cytosol (2). Effectors containing a CaaX box may be prenylated and further modified by other enzymes implicated in the prenylation pathway (3). These modifications may help target bacterial effectors to the cytosolic face of the bacteria-containing vacuole or elsewhere in the host cell (4).