Proteoform: a single term describing protein complexity

By Lloyd M. Smith, N. Kelleher. 2013

1,391 citations recorded by the source corpus.

genetic differences and not to variation at the protein level2. The term “protein species” was proposed in 2009 (ref. 2) but does not distinguish between proteins originating from different genes and those originating from a single gene, and thus we find it confusing. A similar issue arises with the term “protein variants.” The UniProt Knowledgebase (a definitive, gene-centric protein database)5 uses the term “isoform” in yet a different manner, one that denotes related forms of protein molecules arising from the same gene by alternative splicing or variable promoter usage (Fig. 1). Such events create a variable set of protein sequences that significantly change the numbering of amino acids for the protein as compared to the canonical sequence. These changes to the base primary sequence are referred to by some as “isoforms” and are denoted in UniProt by a –1, –2 and so on following the accession number (Fig. 1). However, genetic changes (for example, mutations and polymorphisms) are not covered by this terminology and create a conflict with the IUPAC definition of isoform2. Differences in IUPAC and UniProt definitions notwithstanding, the terms “variants” and “isoforms” were intended to describe proteins derived from distinct DNA or RNA; their use to describe modified proteins is confusing. Accordingly, we propose that the term ‘proteoform’ be used to designate all of the different molecular forms in which the protein product of a single gene can be found, including changes due to genetic variations, alternatively spliced RNA transcripts and posttranslational modifications (Fig. 1). Any gene or protein processing events such as those using inteins or RNA-editing mechanisms are now covered cleanly by the term ‘proteoform’. The term should include all post-translational modifications in the PSI-MOD ontology except those classified as reagent-derivatized or isotope-labeled residues (see the Supplementary Note for a precise definition). Products of multigene families should continue to be categorized on the basis of sequence identity (for example, >90%, >99% and so on). The term is compatible with a gene-centric approach for referring to proteins, which we support, because grouping related forms of proteins together even though they are the products of different genes leads to imprecision in protein identification5. We have begun to use the term ‘proteoform’ in our own writing and presentations, and we find it to be intuitive and readily grasped Proteoform: a single term describing protein complexity

Subfields: Materials Chemistry, Molecular Biology, Spectroscopy

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Citations in the corpus

Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics (2019, background): “Therefore, intrinsic disorder represents a cornerstone of the proteoform concept [94] introduced to explain an important observation that the complexity of a biological system is primarily determined not by the genome size, but by its proteome size [95].”
Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell‐lines (2015, background): “On the one hand, this is due to the sheer complexity of the proteome—where cellular proteins are expressed in a large diversity of isoforms and modiﬁcations, over a huge dynamic range, and in a variety of cellular localizations and biochemical contexts [3,4].”
The Size of the Human Proteome: The Width and Depth (2016, background): “Of the many different terms proposed to describe protein variants [6], here, we chose “protein species” [7] or “proteoforms” [6].”