The intracellular dynamic of protein palmitoylation

Salaun, Christine; Greaves, Jennifer; Chamberlain, Luke H.

Although the Golgi appears to function as a hub for palmitoylation of newly synthesized and cycling peripheral proteins, certain proteins undergo dynamic palmitoylation remodeling without accessing the Golgi. This suggests that active DHHC proteins are localized in post-Golgi compartments. Indeed, DHHC2 and DHHC5 associate with the plasma membrane in neuroendocrine cells (Greaves et al., 2010) , and these proteins are present on post-Golgi membranes in neuronal dendrites and at the postsynaptic density Li et al., 2010) . SNAP25, a multiply palmitoylated peripheral protein, is modified by Golgi-localized DHHC proteins (Fukata et al., 2004 Huang et al., 2004; Greaves et al., 2009a Greaves et al., , 2010 , which palmitoylation site were changed to their stereoisomeric (i.e., D-amino acids) counterparts. The insertion of these D-amino acids, which was predicted to disrupt any specific protein-binding site, had no major effect on Golgi accumulation of the microinjected proteins . Further analysis suggested that there was also not an essential DHHC recognition domain in the remainder of the Ras protein. These observations suggest that the DHHC proteins that modify Ras do not require a specific signature of the palmitoylated domain or upstream region and implies that palmitoylation of peripheral proteins may not be restrained by tight enzyme substrate specificities; the major requirement for palmitoylation presumably being a suitable cysteine in close membrane proximity. However, this idea is not readily consistent with other studies that have highlighted features of both DHHC proteins and substrate proteins that contribute to specificity of interaction (Greaves et al., 2009a (Greaves et al., , 2010 Huang et al., 2009; Nadolski and Linder, 2009) or that identified a requirement for a specific DHHC protein for palmitoylation of a specific substrate (Roth et al., 2006; Ohyama et al., 2007; Stowers and Isacoff, 2007; Emmer et al., 2009; Huang et al., 2009; Noritake et al., 2009; Tian et al., 2010) . Indeed, depletion of a single DHHC protein, Erf2, had a marked impact on the palmitoylation of yeast Ras (Bartels et al., 1999; Roth et al., 2006) . Further work is clearly required to delineate the reasons for these apparent inconsistencies.