Functional determinants of protein assembly into homomeric complexes

Abstract

Approximately half of proteins with experimentally determined structures can interact with other copies of themselves and assemble into homomeric complexes, the overwhelming majority of which (>96%) are symmetric. Although homomerisation is often assumed to a functionally beneficial result of evolutionary selection, there has been little systematic analysis of the relationship between homomer structure and function. Here, utilizing the large numbers of structures and functional annotations now available, we have investigated how proteins that assemble into different types of homomers are associated with different biological functions. We observe that homomers from different symmetry groups are significantly enriched in distinct functions, and can often provide simple physical and geometrical explanations for these associations in regards to substrate recognition or physical environment. One of the strongest associations is the tendency for metabolic enzymes to form dihedral complexes, which we suggest is closely related to allosteric regulation. We provide a physical explanation for why allostery is related to dihedral complexes: it allows for efficient propagation of conformational changes across isologous (i.e. symmetric) interfaces. Overall we demonstrate a clear relationship between protein function and homomer symmetry that has important implications for understanding protein evolution, as well as for predicting protein function and quaternary structure.One of the fundamental challenges in the biological sciences is in understanding the relationship between protein structure and function. This problem is highly relevant not only to the understanding of the evolution of a protein's biological role, but for protein structure and function prediction, protein design, and the prediction of the phenotypic impact of mutations.Within protein families there is enormous functional diversity, and sequences, folds and domains can all code for different functionalities depending on their surroundings 1-3 . In the dynamic and crowded environment that is a living cell 4, 5 , proteins are in constant contact with each other and often carry out their functions as part of larger protein complexes [6][7][8][9] . The way that the subunits are organised to form the quaternary structure of a protein complex is a crucial piece of the protein structure-function relationship puzzle, alongside sequences, folds and domains.Most of the structural information on protein complexes that we have available today is for homomers, i.e. protein complexes that are formed by the assembly of multiple copies of a single type of polypeptide chain. Analysis of published X-ray crystal structures shows that roughly 45% of eukaryotic proteins and 60% of prokaryotic proteins can form homomeric complexes 10 . Whilst the high fraction of homomers does reflect biases in protein structure determination, and the fraction of heteromeric complexes (i.e. those formed from multiple distinct polypeptide chains) within cells is probably higher, homomerisation is ...

A DNA-based synthetic apoptosome

“…A thermodynamic model based on tethered dimerization revealed that the observed activity enhancement partially originates from a statistical increase in the number of active catalytic units in higher-order enzyme configurations. We envision that clustering of catalytic enzymatic subunits into higher-order complexes, either through SMOC-based assembly 4,5 , functional homotypic interactions 62,63 , or via liquid phase separation 64,65 , could represent a general mechanism for enzymatic activity enhancement or regulation in various intracellular processes.…”

Supercharging enables organized assembly of synthetic biomolecules

“…16, 2018; 2 The assembly of genetically-encoded molecules into symmetric, supramolecular materials enables complex functions in natural biosystems and would likewise prove valuable in the development of bionanotechnologies including drug delivery, energy transport, and biological information storage. [1][2][3][4][5][6][7] Repeated, symmetric interactions between molecular building blocks enable the formation of complex, defined, assemblies from a small total number of components as well as dynamic propagation of conformational change. [3][4][5][6][7][8] However, while de novo engineering of artificial symmetrical biomolecular complexes has begun to be explored, 9-15 these efforts generally rely upon precise design of molecular interfaces.…”

“…Given that both natural proteins [3][4][5][6][7][8] and synthetic colloids [18][19][20][21][22][23][24][25][26][27][28][29] have been shown to readily assemble into symmetric, higher order structures, we anticipate that our SuPrA strategy can now be generalized to create synthetic, scalable…”

“…[1][2][3][4][5][6][7] Repeated, symmetric interactions between molecular building blocks enable the formation of complex, defined, assemblies from a small total number of components as well as dynamic propagation of conformational change. [3][4][5][6][7][8] However, while de novo engineering of artificial symmetrical biomolecular complexes has begun to be explored, [9][10][11][12][13][14][15] these efforts generally rely upon precise design of molecular interfaces. 16,17 In contrast, studies of simple synthetic colloids suggests that higher order structures can be derived based solely on packing and energetic and considerations.…”

The inter-dimeric interface controls function and stability ofUreaplasma urealiticummethionine S-adenosyltransferase

“…Based on this analysis, we propose that, whilst the evolutionary ancient and highly conserved dimeric interface of MAT controls its primary enzymatic function and the assembly path of the tetramer, the more recent inter-dimeric interface is recruited by evolution to tune the molecular properties of the entire tetramer and tailor them to the specific needs of the organism. Finally, the existence of the homomer-level modes of regulation of stability and activity that stems from the evolutionary tinkering of the interdimeric interface also provides a clue as to why dihedral homomers exhibit a particularly strong functional enrichment in metabolic enzymes (Bergendahl and Marsh, 2017). a and b, and between chains c and d), and inter-dimeric interface between dimers ab and cd.…”