I don't normally post basic science abstracts here but this one has an important implication for investors in certain types of biotechs, and it seemed too bad to bury it on the underfollowed "-omics" threads . . .
>>Nature. 2004 Jan 15; 427(6971): 252-6.
Immune recognition of a human renal cancer antigen through post-translational protein splicing.
Hanada K, Yewdell JW, Yang JC.
Surgery Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building10, Room 2B42, Bethesda, Maryland 20892, USA. khanada@nih.gov
Cytotoxic T lymphocytes (CTLs) detect and destroy cells displaying class I molecules of the major histocompatibility complex (MHC) that present oligopeptides derived from aberrant self or foreign proteins. Most class I peptide ligands are created from proteins that are degraded by proteasomes and transported, by the transporter associated with antigen processing, from the cytosol into the endoplasmic reticulum, where peptides bind MHC class I molecules and are conveyed to the cell surface. C2 CTLs, cloned from human CTLs infiltrating a renal cell carcinoma, kill cancer cells overexpressing fibroblast growth factor-5 (FGF-5). Here we show that C2 cells recognize human leukocyte antigen-A3 MHC class I molecules presenting a nine-residue FGF-5 peptide generated by protein splicing. This process, previously described strictly in plants and unicellular organisms, entails post-translational excision of a polypeptide segment followed by ligation of the newly liberated carboxy-terminal and amino-terminal residues. The occurrence of protein splicing in vertebrates has important implications for the complexity of the vertebrate proteome and for the immune recognition of self and foreign peptides.<<
emphasis mine
Aside from the implications for immunology and oncology mentioned in the abstract, this also means that deriving targets from gene sequences just got way more unlikely. In addition to post-translational modifications like "-ylation" (i.e. adding something to the product protein, such as a methyl group in methylation), and enzymatic cleavage into fragments, we now find that protein fragments are spliced together. If this proves to be a widespread mechanism in human biology, getting from gene to drug could be much more difficult than it already is. Could this be why folks like Incyte and Lexicon haven't seen results yet from their customers' use of their databases? It also implies a longer road for companies with a proteomics approach to drug discovery. Anybody see it differently?
Wow. Yikes.
Cheers, Tuck |
