Structural and evolutionary versatility in protein complexes with uneven stoichiometry

Marsh, Joseph A.; Rees, Holly A.; Ahnert, Sebastian E.; Teichmann, Sarah A.

doi:10.1038/ncomms7394

Cited by 50 publications

(48 citation statements)

References 62 publications

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“…This can be rationalised by the 2:1 stoichiometry of the interaction between a dimeric DNA-binding protein ( e.g . transcription factor) and the double-stranded DNA, which will be inherently asymmetric unless there is twofold symmetry at the DNA level 10 .…”

Section: Resultsmentioning

confidence: 99%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

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Functional determinants of protein assembly into homomeric complexes

Bergendahl

Marsh

2017

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional determinants of protein assembly into homomeric complexes

Bergendahl

Marsh

2017

Sci Rep

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“…This is especially important for eukaryotic complexes, which have a much greater propensity to form heteromers [44,45], compared with bacterial proteins, which are more likely to self-assemble into homomers [46] or be encoded in operons. Much more work is needed to fully understand how the assembly of heteromeric complexes occurs within eukaryotic cells, both co-and post-translationally and how it is regulated.…”

Section: Perspectivesmentioning

confidence: 98%

Co-translational assembly of protein complexes

Wells

Bergendahl

Marsh

2015

Biochemical Society Transactions

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The interaction of biological macromolecules is a fundamental attribute of cellular life. Proteins, in particular, often form stable complexes with one another. Although the importance of protein complexes is widely recognized, we still have only a very limited understanding of the mechanisms underlying their assembly within cells. In this article, we review the available evidence for one such mechanism, namely the coupling of protein complex assembly to translation at the polysome. We discuss research showing that co-translational assembly can occur in both prokaryotic and eukaryotic organisms and can have important implications for the correct functioning of the complexes that result. Co-translational assembly can occur for both homomeric and heteromeric protein complexes and for both proteins that are translated directly into the cytoplasm and those that are translated into or across membranes. Finally, we discuss the properties of proteins that are most likely to be associated with co-translational assembly.

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“…Both rational mutagenesis and directed evolution have been exploited to advance our understanding of how oligomers form [31][32][33][34], and to design new hetero-oligomers [35,36]. Protein flexibility, shape and symmetry have all been identified as being important for the formation of new oligomeric structure [37,38], since symmetrical and complementary interfaces may form stronger interactions than heterologous surfaces [39][40][41].…”

Section: Introductionmentioning

confidence: 99%

Evolution of Protein Quaternary Structure in Response to Selective Pressure for Increased Thermostability

Fraser

Liu

Mabbitt

et al. 2016

Journal of Molecular Biology

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Oligomerization has been suggested to be an important mechanism for increasing or maintaining the thermostability of proteins. Although it is evident that protein-protein contacts can result in substantial stabilization in many extant proteins, evidence for evolutionary selection for oligomerization is largely indirect and little is understood of the early steps in the evolution of oligomers. A laboratory-directed evolution experiment that selected for increased thermostability in the αE7 carboxylesterase from the Australian sheep blowfly, Lucilia cuprina, resulted in a thermostable variant, LcαE7-4a, that displayed increased levels of dimeric and tetrameric quaternary structure. A trade-off between activity and thermostability was made during the evolution of thermostability, with the higher-order oligomeric species displaying the greatest thermostability and lowest catalytic activity. Analysis of monomeric and dimeric LcαE7-4a crystal structures revealed that only one of the oligomerization-inducing mutations was located at a potential protein-protein interface. This work demonstrates that by imposing a selective pressure demanding greater thermostability, mutations can lead to increased oligomerization and stabilization, providing support for the hypothesis that oligomerization is a viable evolutionary strategy for protein stabilization.

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Structural and evolutionary versatility in protein complexes with uneven stoichiometry

Cited by 50 publications

References 62 publications

Functional determinants of protein assembly into homomeric complexes

Functional determinants of protein assembly into homomeric complexes

Co-translational assembly of protein complexes

Evolution of Protein Quaternary Structure in Response to Selective Pressure for Increased Thermostability

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