The proposal by Smith et al. in their Nature Methods correspondence to adopt the term "proteoform" would somewhat reduce the ambiguity of what is meant by a protein "isoform." Isoforms would primarily arise from alternative splicing of the same gene or, I presume, highly related genes arising from gene duplication that are also functional homologues. "Proteoforms" would encompass all amino acid differences arising from genetic mutations and post-translational modifications of a protein translated from an mRNA according to the definition proposed.

The difficulty with this suggestion is that the term "isoform" has also been historically used to distinguish between proteins that reside in complexes with different subunits. For example, many of the cyclin-dependent protein kinases can each bind to different cyclins. In another example, the catalytic subunit of protein phosphatase 2A can bind to a wide diversity of regulatory subunits that can affect its cellular location and substrate specificity. As defined in the Smith et al. Nature Methods correspondence, these isoforms would not be reclassified as proteoforms. However, if the word "proteoform" was extended to include protein complexes, I think that the meaning of term would be too diluted and it would be overly broad.

The vast majority of proteins in cells appear to exist in either homogeneous or heterogenous multimeric complexes. Perhaps it would be a good idea to adopt a third term to distinguish proteins on the basis of their quaternary structures. Carrying on with the intent of this initiative, I suggest a generalized term "proteocomplex" that refers to the specific composition and stoichiometry of subunits in protein complexes. From a quick Google search, this appears to be a novel word, but I believe that it is conceptually obvious in its meaning.