Evolving views on protein palmitoylation (Comment on DOI 10.1002/bies.201300076)

Abstract

In their Hypotheses article, Thomas and Hayashi [1] engagingly discuss how the evolutionary acquisition of palmitoylation sites may have provided 'add-ons' that extend the capacity to regulate key neuronal proteins. They argue that this increased regulatory capacity may be an important factor in the development of a more complex nervous system during vertebrate evolution.Palmitoylation is a reversible posttranslational modification involving the attachment of palmitate and other fatty acids to cysteine residues. Several hundred neuronal proteins undergo palmitoylation, including AMPA receptors, which mediate fast excitatory glutamate neurotransmission. AMPA receptor levels at the post-synaptic membrane are an important determinant of synaptic strength and plasticity, and it is argued that additional acquired modes of receptor regulation might represent important adaptations in organisms with more complex nervous systems. AMPA receptor subunits are modified by palmitoylation at two sites, the cytosolic boundary of the second transmembrane domain and the cytosolic C-terminus [2]; palmitoylation at both sites regulates cell surface expression, albeit by different mechanisms [2]. Furthermore, palmitoylation also modulates the targeting of proteins that regulate AMPA receptor localisation and function. PSD95 acts as a molecular anchor for several proteins present at post-synaptic regions, and it indirectly tethers AMPA receptors. Preventing the palmitoylation of two cysteines in the N-terminus of PSD95 leads to a loss of this protein from synapses, accompanied by reduced synaptic expression of AMPA receptors [3]. Palmitoylation also controls the targeting of GRIP1b to dendritic endosomes, where it regulates the distribution of AMPA receptors between endosomes and the cell surface [4]. Thomas and Hayashi report that known palmitoylation sites in AMPA receptors, PSD95 and GRIP1b, are mainly restricted to vertebrates. Thus, the acquisition of a multi-layered palmitoylation control of AMPA receptor localisation and function might represent a key adaptation contributing to higher brain function.The authors complement their analysis of palmitoylation substrates by examining palmitoylation enzymes. A family of over twenty 'DHHC' S-acyltransferases regulate cellular palmitoylation dynamics, and enzymes active against AMPA receptor subunits, PSD95 and GRIP1b, have been identified [2,4,5]. Two DHHC enzymes that are active against GRIP1b use C-terminal PDZ ligands to recognise PDZ domains present in this substrate, a mode of enzymesubstrate recognition that is essential for GRIP1b palmitoylation [4]. Although the mechanisms underlying PSD95 recognition by DHHC enzymes have not been delineated, there may be a similar recognition of the PSD95 PDZ domains. If key neuronal proteins have acquired palmitoylation sites during evolution, have the DHHC enzymes acquired the ability to recognise these proteins? In fact, the authors note a marked increase in the fraction of vertebrate DHHC enzymes containing predicted PDZ ligands, compar...