These have now been corrected in the online version of the article. “
“Current Opinion in Chemical Biology 2015, 24:48–57 This review comes from a themed issue on Omics Edited by Benjamin F Cravatt and Thomas Kodadek http://dx.doi.org/10.1016/j.cbpa.2014.10.016 1367-5931/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). Amongst the hundreds of classes of known protein post-translational modification (PTM)

protein Selleck Ion Channel Ligand Library lipidation is unique in enabling direct interaction with cell membranes, ranging from constitutive, stable anchors that can withstand multiple rounds of endosomal recycling, to transient membrane binders that permit rapid switching of subcellular localization. Protein lipidation is found in every form of life, and has evolved to its most sophisticated forms in eukaryotes, in which vesicular trafficking pathways and membrane-bound signaling platforms are strongly regulated by lipidated protein families. These PTMs are also important in disease; many of the enzymes involved in installing and processing protein lipidation have been targeted for

drug discovery, resulting in a number of clinical trials. However, the complex and incompletely understood substrate specificity of these enzymes, and its intricate interplay with lipid metabolism and disease context, have contributed to a challenging and thus far inconclusive development process.

Numerous protein lipidation substrates have been discovered to date, generally through metabolic radiolabeling with lipid precursors, selleck products but the full substrate scope has yet to be determined for any of the known types of lipidation. In particular, very few substrates have been validated at endogenous levels in cells, that is, without resorting to substrate overexpression which may in itself influence lipidation levels, and very little is currently known learn more about how changes induced by genetic mutation, disease or drug treatment quantitatively affect protein lipidation across the proteome. Global profiling of protein lipidation lies beyond the range of most standard bioanalytical methods because these relatively large and very hydrophobic PTMs present challenges in protein isolation and separation, restrict ionization of peptides and proteins during mass spectrometric analysis, and are insensitively labeled by radioactive isotopes. Fortunately, protein lipidation is particularly well-suited to analysis through metabolic chemical tagging, since the large size and hydrophobicity of these PTMs facilitates modification with small ‘clickable’ tags whilst avoiding disruption to metabolism and function (Figure 1) [1, 2 and 3]. These tags can then be addressed either in situ or following protein isolation through one of a set of extremely chemoselective reactions that add multifunctional labels exclusively to the modified proteins.