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23rd Human Proteome Organization World Congress

Microproteins and the non-canonical proteome in childhood cancer

Keynote Lecture

Ribosome profiling (Ribo-Seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of noncanonical sites of ribosome translation outside the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7000 noncanonical ORFs are translated, which, at first glance, has the potential to expand the number of human protein CDSs by 30%, from ~19,500 annotated CDSs to over 26,000 annotated CDSs. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction of those can be understood as proteins according to the conventional understanding of the term. I will discuss the current state of noncanonical ORF research, databases, and interpretation, focusing on how to assess whether a given ORF can be said to be &quot;protein coding.&quot; I will do so in the context of childhood cancer, where strategies targeting the small microproteins produced from these ORFs hold great promise for the development of new (immuno)therapies against these deadly early-onset cancers.

Keynote lecture

Profiling metalloproteomes by chemical and computational proteomics

Metal binding proteins (MBPs) are widely distributed in living systems. They play key roles in diverse biological processes, including but not limited to catalysis, stabilization of proteins&quot; structure, and signal transduction. So far, there are few methods to identify MBPs on the proteome level. In this talk, I will describe our recent and ongoing efforts to profile MBPs in a global scale by chemical and computational proteomics methods1. Our approach identified a large number of previously unannotated MBPs, some of which can be experimentally and structurally validated. Our chemoproteomic and computational methods will provide an enabling tool for discovering more MBPs systematically and the data will generate more hypothesis for the community of studying metal biology.

Proteomics tools facilitate the discovery of the new function of PTMs

Post-translational modification (PTM) regulates protein functions and influence almost all aspects of normal cell biology and pathogenesis. Therefore, identifying and understanding PTMs is crucial in the study of cell biology and disease treatment and prevention. Recently, we have developed a few proteomics tools to facilitate the discovery of the new function of PTMs. A highly robust N-glycoproteomics (HRN) platform comprising an automated enrichment method, a stable microflow LC-MS/MS system, and a sensitive glycopeptide-spectra-deciphering software tool (i.e. Glyco-Decipher) is developed for large-scale quantitative N-glycoproteome analysis, which enabled the identification of over 20,000 unique site-specific glycans and discovered one with good performance in diagnosing early-stage gastric cancer. A methyl-specific metabolic labeling approach was developed for the identification of methylations on 8 types of residues. Interestingly, of the identified methylation events, His methylation is found to be preferably occurred in C3H1 zinc fingers (ZFs). The His methylation is found to stabilize the structure of ZFs. U2AF1 is used as a proof-of-concept to highlight the functional importance of His methylation in ZFs in RNA binding and RNA metabolism. A special limited proteolysis approach, &quot;peptide-centric local stability assay&quot;(PELSA), was developed to enable proteome-wide target identification and binding-region determination of diverse ligands. Beyond offering users unprecedented sensitivity for characterizing diverse target-ligand interactions, it can also be applied to identify the reader proteins of PTMs. This was demonstrated by identifying the target proteins of a synthetic phosphotyrosine peptide pYEEI via using PELSA. It was founs that 28 proteins were significantly stabilized, among which 9 proteins contain SH2 domains, the reading domains for tyrosine phosphorylation. Our results demonstrated that PELSA can be readily applied to investigate the recognition domains of PTMs, which is crucial for understanding the biological functions of the PTMs.

Scientific session 1
Functional diversity of proteoforms

Appointment

Program

Scientific session 1Functional diversity of proteoforms

Appointment

Program

Scientific session 1
Functional diversity of proteoforms