Lessons from equilibrium statistical physics regarding the assembly of protein complexes

Abstract

Cellular functions are established through biological evolution, but are constrained by the laws of physics. For instance, the physics of protein folding limits the lengths of cellular polypeptide chains. Consequently, many cellular functions are carried out not by long, isolated proteins, but rather by multiprotein complexes. Protein complexes themselves do not escape physical constraints, one of the most important being the difficulty of assembling reliably in the presence of cellular noise. In order to lay the foundation for a theory of reliable protein complex assembly, we study here an equilibrium thermodynamic model of self-assembly that exhibits 4 distinct assembly behaviors: diluted protein solution, liquid mixture, "chimeric assembly," and "multifarious assembly." In the latter regime, different protein complexes can coexist without forming erroneous chimeric structures. We show that 2 conditions have to be fulfilled to attain this regime: 1) The composition of the complexes needs to be sufficiently heterogeneous, and 2) the use of the set of components by the complexes has to be sparse. Our analysis of publicly available databases of protein complexes indicates that cellular protein systems might have indeed evolved so as to satisfy both of these conditions. self-assembly | protein complex

Analysing the Yeast Complexome - The Complex Portal rising to the challenge

“…Most of the proteins found in more than one complex are core subunits of complexes of which many different variants exist, such as cyclin-dependent kinases or ubiquitin ligases. In a recent analysis of datasets from several yeast interactome datasets it was demonstrated that this long right-hand tail of a few proteins occurring in many complexes is almost always significantly different from a random distribution (37). The random distribution estimates that proteins should be found in a maximum of 6-9 complexes while in the real data some proteins occur in >20 complexes, matching our observations.…”

“…To date, the Complex Portal yeast complexome has been used to validate complexes in several large-scale studies (37,(39)(40)(41)(42) As we move to complete more complexomes, for example that of Escherichia coli, and continually improve our coverage of the human and mouse complexes, it will also be possible to improve our understanding of the evolution of these assemblies (50), and from there how the regulation of cellular processes has developed as organisms evolve.…”

“…To date, the Complex Portal yeast complexome has been used to validate complexes in several large-scale studies (37, 39–42) and our stable identifiers are used as annotation objects and cross-references in several other curated databases, such as IMEx consortium partners, Gene Ontology (43), Genome Properties (44), MatrixDB (45), SGD (13), Reactome, Signor (46, 47) and Wikipathways (48) while other collaborations are under development, e.g. with PDBe (49).…”

Analysing the yeast complexome—the Complex Portal rising to the challenge

“…A check against the GO annotation of these proteins showed that many are catalytic core subunits of complexes such as cyclin-dependent kinases or ubiquitin ligases. In a recent analysis of datasets from several yeast interactome datasets, it was demonstrated that this long right-hand tail of a few proteins occurring in many complexes is almost always significantly different from a random distribution ( 38 ). The random distribution estimates that proteins should be found in a maximum of 6–9 complexes while in the real data some proteins occur in >20 complexes, matching our observations.…”

Handhold-mediated strand displacement: a nucleic acid-based mechanism for generating far-from-equilibrium assemblies through templated reactions

“…Without templating of far-from-equilibrium ensembles it would be impossible to achieve the chemical complexity of biology. For example, there simply cannot be enough information stored in the interactions between 20 basic building blocks (the standard amino acids) to code for the selective assembly of tens of thousands of specific proteins -and only those proteins -from a mixture of only these amino acids 16 . Far-from-equilibrium templating solves this problem by providing a reusable mechanism to assemble an arbitrary polypeptide chain.…”