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Submitted on March 6, 2005
Revised on April 27, 2005
Accepted on April 28, 2005

Precise and parallel characterization of coding polymorphisms, alternative splicing and modifications in human proteins by mass spectrometry

Michael J. Roth, Andrew J. Forbes, Michael T. Boyne . II, Yong-Bin Kim, Dana E. Robinson, and Neil L. Kelleher

Department of Chemistry, University of Illinois, Urbana, IL 61801

Corresponding Author: kelleher{at}scs.uiuc.edu

The human proteome is a highly complex extension of the genome wherein a single gene often produces distinct protein forms due to alternative splicing, RNA-editing, polymorphisms, and posttranslational modifications (PTMs). Such biological variation compounded by the high sequence identity within gene families currently overwhelms the complete and routine characterization of mammalian proteins by mass spectrometry (MS). A new database of human proteins (and their possible variants) was created and searched using tandem mass spectrometric data from intact proteins. This first application of Top Down MS/MS to wild-type human proteins demonstrates both gene-specific identification and the unambiguous characterization of multi-faceted mass shifts. Such discrepancies found from the precise identification of 45 protein forms from HeLa cells reveal 34 coding SNPs, two protein forms from alternative splicing, and 12 diverse modifications (not including simple N-terminal processing), including a previously unknown phosphorylation at 10% occupancy. Automated protein identification was achieved with a median probability score of 10-13 and often occurred simultaneously with dissection of diverse sources of protein variability as they occur in combination. Top Down MS therefore has a bright future for enabling precise annotation of gene products expressed from the human genome by non-mass specrometrists.


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