Abstract
Despite direct or indirect efforts of the proteomic community, the fraction of blind spots on the protein map is still significant. Almost 11% of human genes encode missing proteins; the existence of which proteins is still in doubt. Apparently, proteomics has reached a stage when more attention and curiosity need to be exerted in the identification of every novel protein in order to expand the unusual types of biomaterials and/or conditions. It seems that we have exhausted the current conventional approaches to the discovery of missing proteins and may need to investigate alternatives. Here, we present an approach to deciphering missing proteins based on the use of non-standard methodological solutions and encompassing diverse MS/MS data, obtained for rare types of biological samples by members of the Russian Proteomic community in the last five years. These data were re-analyzed in a uniform manner by three search engines, which are part of the SearchGUI package. The study resulted in the identification of two missing and five uncertain proteins detected with two peptides. Moreover, 149 proteins were detected with a single proteotypic peptide. Finally, we analyzed the gene expression levels to suggest feasible targets for further validation of missing and uncertain protein observations, which will fully meet the requirements of the international consortium. The MS data are available on the ProteomeXchange platform (PXD014300).
Highlights
The chromosome-centric “Human Proteome” project (C-Human Proteome Project (HPP)) celebrates its 10th anniversary in2020
The speed of proteome deciphering by efforts of the International Consortium is not constant: the less proteins are missing, the more determination, ingenuity, and time is required for the detection of the one missing protein
To assess changes in the rate of missing proteins detection over time we performed a comparative analysis of versions of the neXtProt platform, the main aggregator of proteomic data in the framework of the Human Proteome Project (HPP) [26]
Summary
The chromosome-centric “Human Proteome” project (C-HPP) celebrates its 10th anniversary in2020 (http://www.c-hpp.org/ [1]). The major goal of the project is to detect previously unreported (missing) proteins [2], since the lack of experimental evidence of gene products at the protein level casts doubt on the functional significance of the corresponding protein-coding genes. Proteomes 2020, 8, 12 constitutes 10.7% of the human master proteome (where at least one protein product is detected per each protein-coding gene [3]) and includes 2129 missing proteins with transcript (PE2), homological (PE3) or prediction (PE4) statuses, and 576 uncertain proteins (PE5) support of “protein existence”, according to the neXtProt tiers A more effective project realization may be required to deviate from the chromosome-centric approach and to concentrate efforts on the exploration of the hidden part of proteome, without referring to a certain chromosome. The detectability of such proteins is associated with the number of methodological and biological challenges [6], namely, with the conservation level of the protein sequence, availability for proteases, ionizability of proteotypic peptides, exposure to mutations and modifications, and the exploration degree and specificity of the tissue under study
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