Proteoforms in human health and disease

Seminar | February 20 | 12-1 p.m. | 106 Stanley Hall

 Neil Kelleher, Northwestern University

 Bioengineering (BioE)

Proteoforms are the specific molecular forms of proteins arising from human genes encoded in the human genome. They include all sources of protein variation, and here’s a list: sequence mutations, alternative splicing, and post-translational modifications (PTMs). They underlie diverse biological systems and proteoform diversity is directly linked to functions, pathway modulation, and disease state. Our lab seeks to regularize the compositional human proteome which has perhaps a million different forms of proteins within a given cell type. Though proteoform complexity is high, it seems nowhere near theoretical limits based on the simplistic 2n scaling from combinatorial modification (where n is the number of PTMs). However, the number and variety of proteoforms in biological systems is hotly debated, and some sense of this along with related topics will be provided in this brief seminar. Our lab uses Top Down Proteomics (TDPs), which analyzes intact proteins directly (no protein digestion, e.g., with trypsin) using protein fractionation, mass spectrometry, and bioinformatics. TDP is coming of age for the identification, characterization, and direct quantification of proteoforms with total molecular specificity and recent applications of TDPs in translational research across cancer biology, heart disease and neurology will be surveyed.