Progress and pitfalls in finding the ‘missing proteins’ from the human proteome map

Segura, Víctor; Garin-Muga, Alba; Guruceaga, Elizabeth; Corrales, Fernando J.

doi:10.1080/14789450.2017.1265450

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…those still in P2 to P5) that remain refractory to tryptic peptide verification at the necessary stringency. This aspect has been the subject of several recent reviews and so does not need expanding here 18, 19 .…”

Section: Existence Evidencementioning

confidence: 99%

Last rolls of the yoyo: Assessing the human canonical protein count

Southan

2017

F1000Res

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In 2004, when the protein estimate from the finished human genome was only 24,000, the surprise was compounded as reviewed estimates fell to 19,000 by 2014. However, variability in the total canonical protein counts (i.e. excluding alternative splice forms) of open reading frames (ORFs) in different annotation portals persists. This work assesses these differences and possible causes. A 16-year analysis of Ensembl and UniProtKB/Swiss-Prot shows convergence to a protein number of ~20,000. The former had shown some yo-yoing, but both have now plateaued. Nine major annotation portals, reviewed at the beginning of 2017, gave a spread of counts from 21,819 down to 18,891. The 4-way cross-reference concordance (within UniProt) between Ensembl, Swiss-Prot, Entrez Gene and the Human Gene Nomenclature Committee (HGNC) drops to 18,690, indicating methodological differences in protein definitions and experimental existence support between sources. The Swiss-Prot and neXtProt evidence criteria include mass spectrometry peptide verification and also cross-references for antibody detection from the Human Protein Atlas. Notwithstanding, hundreds of Swiss-Prot entries are classified as non-coding biotypes by HGNC. The only inference that protein numbers might still rise comes from numerous reports of small ORF (smORF) discovery. However, while there have been recent cases of protein verifications from previous miss-annotation of non-coding RNA, very few have passed the Swiss-Prot curation and genome annotation thresholds. The post-genomic era has seen both advances in data generation and improvements in the human reference assembly. Notwithstanding, current numbers, while persistently discordant, show that the earlier yo-yoing has largely ceased. Given the importance to biology and biomedicine of defining the canonical human proteome, the task will need more collaborative inter-source curation combined with broader and deeper experimental confirmation in vivo and in vitro of proteins predicted in silico. The eventual closure could be well be below ~19,000.

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Section: Existence Evidencementioning

confidence: 99%

Last rolls of the yoyo: Assessing the human canonical protein count

Southan

2017

F1000Res

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“…Using TAILS and thus specifically focusing on protein N-termini allowed the researchers to substantially reduce sample complexity in order to improve the detection of low-abundance proteins. In this way, the authors were able to identify 1369 N-terminal peptides from 1234 proteins, 281 of which were novel erythrocyte proteins while six previously-missing proteins [172,173] were identified by MS for the first time [174]. The same group also analyzed human dental pulp as a unique tissue that could lead to the identification of additional missing proteins, and found that most of the identified N-termini represented proteolytic cleavage sites [175].…”

Section: Analyzing Endogenous Proteolytic Cleavage (Proteolysis) In Cmentioning

confidence: 99%

Detecting post-translational modification signatures as potential biomarkers in clinical mass spectrometry

Mnatsakanyan

Shema

Basik

et al. 2018

Expert Review of Proteomics

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Numerous diseases are caused by changes in post-translational modifications (PTMs). Therefore, the number of clinical proteomics studies that include the analysis of PTMs is increasing. Combining complementary information-for example changes in protein abundance, PTM levels, with the genome and transcriptome (proteogenomics)-holds great promise for discovering important drivers and markers of disease, as variations in copy number, expression levels, or mutations without spatial/functional/isoform information is often insufficient or even misleading. Areas covered: We discuss general considerations, requirements, pitfalls, and future perspectives in applying PTM-centric proteomics to clinical samples. This includes samples obtained from a human subject, for instance (i) bodily fluids such as plasma, urine, or cerebrospinal fluid, (ii) primary cells such as reproductive cells, blood cells, and (iii) tissue samples/biopsies. Expert commentary: PTM-centric discovery proteomics can substantially contribute to the understanding of disease mechanisms by identifying signatures with potential diagnostic or even therapeutic relevance but may require coordinated efforts of interdisciplinary and eventually multi-national consortia, such as initiated in the cancer moonshot program. Additionally, robust and standardized mass spectrometry (MS) assays-particularly targeted MS, MALDI imaging, and immuno-MALDI-may be transferred to the clinic to improve patient stratification for precision medicine, and guide therapies.

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“…However, insufficient coverage may also be important for novel peptides or for isoform detection [57]. (iii) Highly hydrophobic proteins (such as olfactory receptors, membrane proteins and highly insoluble proteins), which are estimated to represent 20–30% of the total encoded human proteome, are notoriously difficult to identify by MS [58–61]. (iv) The MPs may result from low-resolution mass analysis [59] (v) Rare proteins are produced only at specific times and in specific cells.…”

Section: Challenges For the C-hppmentioning

confidence: 99%

Advances in the Chromosome-Centric Human Proteome Project: looking to the future

Paik

Omenn

Hancock

et al. 2017

Expert Review of Proteomics

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Introduction: The mission of the Chromosome-Centric Human Proteome Project (C-HPP), is to map and annotate the entire predicted human protein set (~20,000 proteins) encoded by each chromosome. The initial steps of the project are focused on “missing proteins (MPs)”, which lacked documented evidence for existence at protein level. In addition to remaining 2,579 MPs, we also target those annotated proteins having unknown functions, uPE1 proteins, alternative splice isoforms and post-translational modifications. We also consider how to investigate various protein functions involved in cis-regulatory phenomena, amplicons lncRNAs and smORFs. Areas covered: We will cover the scope, historic background, progress, challenges and future prospects of C-HPP. This review also addresses the question of how we can best improve the methodological approaches, select the optimal biological samples, and recommend stringent protocols for the identification and characterization of MPs. A new strategy for functional analysis of some of those annotated proteins having unknown function will also be discussed. Expert commentary: If the project moves well by reshaping the original goals, the current working modules and team work in the proposed extended planning period, it is anticipated that a progressively more detailed draft of an accurate chromosome-based proteome map will become available with functional information.

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Progress and pitfalls in finding the ‘missing proteins’ from the human proteome map

Cited by 12 publications

References 44 publications

Last rolls of the yoyo: Assessing the human canonical protein count

Last rolls of the yoyo: Assessing the human canonical protein count

Detecting post-translational modification signatures as potential biomarkers in clinical mass spectrometry

Advances in the Chromosome-Centric Human Proteome Project: looking to the future

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