"Protein" no longer means what it used to

Abstract

Every biologist knows that the word protein describes a group of macromolecules essential to sustain life on Earth. As biologists, we are invariably trained under a protein paradigm established since the early twentieth century. However, in recent years, the term protein unveiled itself as an euphemism to describe the overwhelming heterogeneity of these compounds. Most of our current studies are targeted on carefully selected subsets of proteins, but we tend to think and write about these as representative of the whole population. Here we discuss how seeking for universal definitions and general rules in any arbitrarily segmented study would be misleading about the conclusions. Of course, it is not our purpose to discourage the use of the word protein. Instead, we suggest to embrace the extended universe of proteins to reach a deeper understanding of their full potential, realizing that the term encompasses a group of molecules very heterogeneous in terms of size, shape, chemistry and functions, i.e. the term protein no longer means what it used to.

Keywords: Heterogeneity; Native state; Protein types.

Fig. 1

Major protein types described in the text. A. Wild type sperm whale myoglobin as a typical example of globular proteins, well populated in secondary structure as well as in a hydrophobic core (PDB ID 5iks). B. Type III collagen containing three interwounded helix, as an example of fibrillar protein (3dmw). C. Elongation factor Tu showing three different domains. Each of these domains are segments that can adopt its fold independently of the rest of the protein (2c78). D. The mouse ribonuclease inhibitor is an example of a repetitive protein of the class α/ß solenoid (3tsr). E. Human fibronectin as an example of a globular protein with domain repeats (3t1w). F. Structure of the UDP-N-acetylglucosamine acyltransferase as an example of a protein containing a left-handed β-helix with unusual left-handed connections (1lxa). G. Crystal structure of bovine pancreatic ribonuclease A as an example of 3D domain-swapp. The N-terminal helix of each subunit (green and cyan) is swapped into the major domain of the other subunit. H. Structure of Acidocin B, a circular bacteriocin, an antimicrobial ribosomally synthesized peptide, from Lactobacillus acidophilus M46 (2mwr). I. Human carbonic anhydrase IX catalytic domain as an example of a knotted protein displaying a trefoil knot (6y74). Knot regions (cyan) and knot range (red) are displayed following its annotation in KnotProt 2.0 database. J. Crystal structure of crambin, a small seed storage protein (just 46 amino acid long) (3nir). K. Cryo-electron microscopy structure of plant mitochondrial respiratory complex I from Brassica oleracea as an example of large multi-chain assembly containing 44 unique proteins (7a23). L An example of a supramolecular structure, the ribosome 80 ​S subunit from Homo sapiens with 76 different protein chains and 5 RNAs (6ek0). M. Highly symmetric protein with a 27-fold symmetric pore known as Gasdermin A3 (6cb8). N. Cellulose cel48 ​F from Clostridium cellulolyticum is an example of a rigid protein, showing conformational diversity only at the residue level that allows open and close of tunnels (in cyan) for the transit of the substrate (1f9d). O. Calmodulin, a Ca2++ sensor protein, is a hub protein that can interact with more than 350 partners and display large conformational diversity, although it is commonly considered an ordered protein (two different conformers, 1niw in green, 1lin in cyan). P. Higher conformational changes can be obtained by hinge motions as between the open and closed structures of the type-C inorganic pyrophosphatases from Streptococcus gordonii (1k20 in green or closed conformer, 1k23 in cyan or open conformer). Q. Alternative extreme conformational changes involving secondary structural elements in CLIC1 protein from Homo sapiens as an example of fold-switching proteins (1rk4, 1k0n). Both structures are represented in cyan while their structural differences are colored in red and green. R. The NMR derived conformational ensemble of sclerostin, a secreted glycoprotein with a key negative regulatory role in Wnt signaling in bone. Sclerostin has two highly flexible N- and C-terminal regions with more than 50% of the protein being disordered (2k8p). S and T. Transthyretin, a thyroid hormone-binding protein that can adopt two very different conformations, a wild-type tetrameric form (4mrb in cyan) and one found in human diseases adopting an amyloid fibril (2m5n in green). U. Several proteins can adopt the same amyloid fibrils but as their main functional state, such as the human peptide hormone glucagon (6nzn).