clip.ubc.ca/topfind/proteins/P05067#processing), for example of the N-APP species by meprin β [53]. However, even the simplified version depicted in Figure 4 highlights the complexity of the different functional and disease outcomes associated with different APP species. Clearly

then, conventional shotgun proteomics cannot easily allow for distinguishing which APP species gave rise to a specific peptide and thus fails to capture this complexity and providing only incomplete information. This void CAL-101 purchase can be filled by identification and quantification of the protein termini which allows not only for dissection of the different species present but also to infer their function and the proteolytic process by which they were generated. If the protease concerned is Bcr-Abl inhibitor a drug target then specific monitoring of these

terminal peptides forms an invaluable biomarker for drug efficacy and treatment progression. Unfortunately knowledge of one terminus is not always enough to unambiguously identify a protein species. For example, to differentiate the pathophysiological differing species Aβ40N672-C711and Aβ42N672-C713 additional knowledge of their C-terminus is required (Figure 4). Thus, in complex mixtures terminomics faces the same limitations as classical shotgun proteomics but while incredible advances have been made in top-down analyses [50••] they are still not readily available. So for now we can conclude that knowledge of the N-terminus and/or C-terminus reveals important information about a protein species including, first, the proteolytic processes leading to its formation; second, the protein features present and lost; third, its functional competence; fourth, and often its predicted stability and thus is essential for generating biologically relevant hypotheses on the protein’s

function in vivo. The advent of proteomics for the enrichment and investigation of protein termini triggered a number of exiting findings and developments. First, when the investigation of limited proteolysis on a proteome-wide level became amenable this resulted Bacterial neuraminidase in an explosion of newly identified protease substrates, an unexpected number of which are protease inhibitors or proteases themselves. This in turn enforced our understanding of proteolysis as a process occurring in a tightly interdependent network we have termed the protease web. With characterization of specificity and in vivo kinetics, great advances have also been made on the level of the individual enzyme in vivo. One area that holds great potential, indeed well deserving of greater attention, is the global characterization of terminal modifications other than N-acetylation, in particular for carboxy-terminal modifications. These are particularly interesting and their unique properties — there is only one of each per protein chain and they only can come into existence after proteolytic processing — add a fascinating level of regulatory complexity.