Science Advances: The Human Proteoform Project: Defining the human proteome, 2021, Lloyd M. Smith et al

The Human Proteoform Project: Defining the human proteome

Lloyd M. Smith, Jeffrey N. Agar, Julia Chamot-Rooke, Paul O. Danis, Ying Ge, Joseph A. Loo, Ljiljana Paša-Tolić, Yury O. Tsybin, Neil L. Kelleher


Abstract
Proteins are the primary effectors of function in biology, and thus, complete knowledge of their structure and properties is fundamental to deciphering function in basic and translational research. The chemical diversity of proteins is expressed in their many proteoforms, which result from combinations of genetic polymorphisms, RNA splice variants, and posttranslational modifications. This knowledge is foundational for the biological complexes and networks that control biology yet remains largely unknown. We propose here an ambitious initiative to define the human proteome, that is, to generate a definitive reference set of the proteoforms produced from the genome. Several examples of the power and importance of proteoform-level knowledge in disease-based research are presented along with a call for improved technologies in a two-pronged strategy to the Human Proteoform Project.

The Human Genome Project (HGP) was a remarkable and unqualified success profoundly transforming and accelerating biological and medical research while converting a ~ $4B public investment into over $700B of economic activity and new industries (1). The challenge of revealing the “Blueprints of Life,” however, is surpassed by the challenge we face today: deriving from these blueprints an understanding of the structures they dictate and how these function within biological systems.

Proteins are primary effectors of function in biology, and thus, complete knowledge of their structure and behavior is fundamental to deciphering function in basic and translational research (2). The richness of protein structure and function goes far beyond the linear amino acid sequence dictated by the genetic code. Genetic variation, alternative splicing, and posttranslational modification (PTM) work together to create a rich variety of different proteoforms arising from our genes (Fig. 1) (3). The chemical diversity of proteins is foundational for the biological complexes and networks that control biology yet remains largely unknown. Genome sequence alone does not provide the needed information—only direct analysis of the proteoforms themselves can reveal their composition, enabling studies of their spatial distributions and temporal dynamics in biological systems. We propose here an ambitious initiative to define the human proteome, that is, to generate a definitive set of reference proteoforms produced from the genome (see Box 1).

Box 1. What is a proteome?
A standard answer to this question is that a proteome is the set of proteins expressed by an organism. This idea clearly depends on what is meant by a “protein.” Proteins from even a single gene can vary widely in their amino acid sequence and PTMs giving rise to a variety of proteoforms. Thus, the proteome is necessarily the set of all proteoforms expressed by an organism. The initiative proposed here is founded upon this simple idea.

https://www.science.org/doi/10.1126/sciadv.abk0734