6472 Traveling to the Ends of the Proteome World with Terminomics and Degradomics

Friday, February 17, 2012: 8:00 AM
Room 109 (VCC West Building)
Christopher Mark Overall , University of British Columbia, Vancouver, BC, Canada
Among the most fundamental characteristics of a protein are the termini defining the start (amino (N) terminus) and end (carboxy (C) terminus) of the polypeptide chain. While genetically encoded, protein termini isoforms are also often generated during translation, following which, termini are highly dynamic, being frequently trimmed at their ends by a large array of exopeptidases. Neo-termini can also be generated by endopeptidases after precise and limited proteolysis, termed processing. Necessary for the maturation of many proteins, processing can also occur after synthesis and maturation, often resulting in dramatic functional consequences. For example chemokine signaling networks can be completely switched by inflammatory cell proteases. Hence, global approaches for the identification and analysis of protein terminal peptides provides key information on the stability and function of most proteins and hence, the functional state of the proteome. New proteomics methods will be presented that enrich and annotate terminomes for high throughput analyses of human tissues and cells for the Human Proteome Project, in particular for ch6 that is one of Canada’s aims for the HPP—Terminal Amino Isotopic Labelling of Substrates (TAILS, Kleifeld et al Nature Biotech 28, 281-288; Prudova et al 2010 Mol Cell Proteomics) and C-TAILS for the C-terminome (Schilling et al Nature Methods 2010). One unexpected result has been the recognition of the extensive number of “moonlighting” proteins—proteins traditionally thought to be located in one cellular compartment such as the cytosol, but which can also have bone fide and often completely different roles extracellularly, and vice versa. Our knowledgebase TopFIND (http://clipserve.clip.ubc.ca/topfind) integrates information on N and C-termini, protease cleavage sites and N-terminal modifications and reveals surprisingly widespread modification and truncation of N and C-termini in 4 model species. Notably, we find that one third of the stable chains in a proteome start distal to the expected protein maturation sites such as initiator methionine, signal peptide and pro-peptide removal points. Since the function of a protein can be entirely switched by proteolysis the implications of this are profound for understanding the functional state of a protein, its place in a network and hence the functional state of the proteome. Thus, knowledge of an organism from genomic data alone is far from complete—the proteome, as well as the termini of the constituent proteins must be recognized and the functional implications understood.
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