Co-translational assembly of protein complexes

Wells, Justin; Bergendahl, L. Therese; Marsh, Joseph A.

doi:10.1042/bst20150159

“…at the N- rather than C-terminus, increases the propensity for assembly to occur during, or soon after translation. Although such early assembly may be beneficial for some proteins6,23, it can also lead to misassembly due to an increase in nonspecific interactions between partially unfolded nascent chains (Figure 1). …”

Section: Resultsmentioning

confidence: 99%

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Natan¹,

Endoh

²

,

Haim-Vilmovsky

³

et al. 2018

Nat Struct Mol Biol

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Cotranslational protein folding can facilitate rapid formation of functional structures. However, it might also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched towards the C-termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur prior to assembly. Using high-throughput imaging of protein homomers in vivo in E. coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization.

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“…An axis of rotation perpendicular to the membrane plane would imply that the different subunits would be in the same relative position with respect to the membrane bilayer. This set-up has been suggested to be a simplification of the insertion process of the protein in the membrane 13 , although membrane complexes have also been observed to form co-translationally 40 . Whilst the much larger set of C 2 complexes is found to associate with a large variety of functions, processes and structures, higher-order cyclic complexes are significantly specialised towards functions that require some type of directionality and/or the formation of a channel structure.…”

Section: Resultsmentioning

confidence: 99%

Functional determinants of protein assembly into homomeric complexes

Bergendahl

¹

,

Marsh

²

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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“…This set-up has been suggested to be a simplification of the insertion process of the protein in the membrane 13 , although membrane complexes have also been observed to form co-translationally 37 . Whilst the much larger set of C 2 complexes is found to associate with a large variety of functions, processes and structures, higher-order cyclic complexes are significantly specialised towards functions that require some type of directionality and/or the formation of a channel structure.…”

Section: Higher-order Cyclic Homomersmentioning

confidence: 99%

“…This is consistent with, for example, the modular view of transcription factors, where the specific DNA-binding regions can only bind to DNA once a transcription factor dimer has been formed 35 . In Figure 1a, the C 2 symmetrical DNA-binding domain of human HSF2 is used as an illustration 36 .…”

Section: Symmetric Dimersmentioning

confidence: 99%

Functional determinants of protein assembly into homomeric complexes

Bergendahl

¹

,

Marsh

²

2016

Preprint

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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.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 ...

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Co-translational assembly of protein complexes

Cited by 33 publications

References 46 publications

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Functional determinants of protein assembly into homomeric complexes

Functional determinants of protein assembly into homomeric complexes

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