Fatty acyl donor selectivity in membrane bound O-acyltransferases and communal cell fate decision-making

Abstract

The post-translational modification of proteins with lipid moieties confers spatial and temporal control of protein function by restricting their subcellular distribution or movement in the extracellular milieu. Yet, little is known about the significance of lipid selectivity to the activity of proteins targeted for such modifications. Membrane bound O-acyl transferases (MBOATs) are a superfamily of multipass enzymes that transfer fatty acids on to lipid or protein substrates. Three MBOATs constitute a subfamily with secreted signalling molecules for substrates, the Wnt, Hedgehog (Hh) and Ghrelin proteins. Given their important roles in adult tissue homoeostasis, all three molecules and their respective associated acyltransferases provide a framework for interrogating the role of extracellular acylation events in cell-to-cell communication. Here, we discuss how the preference for a fatty acyl donor in the Wnt acyltransferase porcupine (Porcn) and possibly in other protein lipidation enzymes may provide a means for coupling metabolic health at the single cell level to communal cell fate decision-making in complex multicellular organisms.

Figure 1. The role of fatty acylation in Wnt and Hh signalling

(A) Porcn utilizes a palmitoleoyl–CoA donor to modify Wnt molecules. Sources of palmitoleoyl–CoA include SCD-mediated desaturation of palmitoyl–CoA. Acylated Wnt protein is chaperoned by the Wntless (Wls) multipass receptor to the cell surface. Secreted Wnt proteins then bind to Fzd receptors with the acyl moiety inserting into a groove found in the extracelluar cysteine-rich domain. (B) Hh molecules are dually lipidated with a cholesterol adduct on the C-terminal domain and a palmitate on the N-terminal domain. Palmitoylation of Hh is mediated by the Hhat. Acylated Hh proteins are released from the membrane by the multipass protein Disp and form multimeric complexes which enable long-range signalling and support formation of graded Hh responses in cells surrounding the ligand producing cells. Hh binding to the Ptch receptor lifts the inhibitory action of Ptch on Smoothened (Smo) thus resulting in transcriptional activation of Hh target genes.

Figure 2. Mechanisms underlying MBOAT acyl donor selectivity

Wnt fatty acylation by the Porcn enzyme is modelled here.