Functional determinants of protein assembly into homomeric complexes

Bergendahl, L. Therese; Marsh, Joseph A.

doi:10.1038/s41598-017-05084-8

Cited by 59 publications

(52 citation statements)

References 60 publications

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“…44 There are symmetry arguments for the apparent over-representation of homodimers in the functional protein universe. 45 Thus, we suspect that heterodimerization in NF κ B has been selected by evolution to be the dominant form, thanks to its manifesting a more beneficial trade-off between thermodynamic stability and allosteric functional DNA binding that is needed to allow kinetic control of a large genetic broadcasting network. 7 …”

Section: Resultsmentioning

confidence: 99%

Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors

et al. 2017

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Many eukaryotic transcription factors function after forming oligomers. The choice of protein partners is a nonrandom event that has distinct functional consequences for gene regulation. In the present work we examine three dimers of transcription factors in the NFκB family: p50p50, p50p65, and p65p65. The NFκB dimers bind to a myriad of genomic sites and switch the targeted genes on or off with precision. The p65p50 heterodimer of NFκB is the strongest DNA binder, and its unbinding is controlled kinetically by molecular stripping from the DNA induced by IκB. In contrast, the homodimeric forms of NFκB, p50p50 and p65p65, bind DNA with significantly less affinity, which places the DNA residence of the homodimers under thermodynamic rather than kinetic control. It seems paradoxical that the heterodimer should bind more strongly than either of the symmetric homodimers since DNA is a nearly symmetric target. Using a variety of energy landscape analysis tools, here we uncover the features in the molecular architecture of NFκB dimers that are responsible for these drastically different binding free energies. We show that frustration in the heterodimer interface gives the heterodimer greater conformational plasticity, allowing the heterodimer to better accommodate the DNA. We also show how the elastic energy and mechanical strain in NFκB dimers can be found by extracting the principal components of the fluctuations in Cartesian coordinates as well as fluctuations in the space of physical contacts, which are sampled via simulations with a predictive energy landscape Hamiltonian. These energetic contributions determine the specific detailed mechanisms of binding and stripping for both homo- and heterodimers.

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Section: Resultsmentioning

confidence: 99%

Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors

et al. 2017

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“…Our simulated evolution of the duplication of HMs leads to the proposal of a simple mechanism for the maintenance of HET that does not require adaptive mechanisms. A large fraction of HMs and HETs use the same binding interface (Bergendahl and Marsh, 2017) and as a consequence, negative selection on HM interfaces will also preserve HET interfaces. Our results show that mutations have correlated effects on HM and HET, which slows down the evolution of independent complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Altogether, these hypotheses imply that the retention of paralogs after duplication is more likely for HM proteins due to the enhanced probability of gain of functions. For example, symmetrical HM proteins could have key advantages over monomeric ones for protein stability and regulation (André et al, 2008;Bergendahl and Marsh, 2017). Levy and Teichmann (Levy and Teichmann, 2013) suggested that the duplication of HM proteins serves as a seed for the growth of protein complexes that allow their diversification by creating asymmetry in the complexes and the recruitment of other proteins, leading to their specialization.…”

Section: Discussionmentioning

confidence: 99%

“…If we assume that HMs need to self-interact to perform their function, it is expected that natural selection favors the maintenance of self-assembly. A large fraction of HMs and HETs use the same binding interface (Bergendahl and Marsh, 2017). This shared interface could create a correlation between the effects of mutations affecting HMs and HETs, making mutations pleiotropic with respect to the two complexes.…”

Section: Pleiotropy Contributes To Maintain Hetsmentioning

confidence: 99%

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The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs

Marchant

Cisneros

Dubé

et al. 2019

Preprint

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Many paralogs derive from the duplication of genes encoding homomeric proteins. Such duplication events lead to the formation of homomers and heteromers, thus creating new structures from a single event. We exhaustively characterize this phenomenon using the budding yeast protein-protein interaction network. We observe that paralogs that heteromerize are very frequent and less functionally diverged than those that lost this property, raising the possibility that heteromerization prevents functional divergence. Using in silico evolution, we show that for homomers and heteromers that share binding interfaces, mutations on one complex have pleiotropic effects on the other complex, resulting in highly correlated responses to selection. As a result, heteromerization could be preserved indirectly due to selection for the maintenance of homomers. By integrating data on gene expression and protein localization, we find that regulatory evolution could play a role in overcoming these structural pleiotropic effects and in allowing paralog functional divergence.

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“…7C). In addition, a relevant study showed that approximately half of the proteins could interact with other copies of themselves and assemble into homomeric complexes, which was often assumed to be a functionally beneficial result of evolutionary selection (11).…”

Section: Evolution Of Nidovirus Endoribonucleasementioning

confidence: 99%

Insight into the evolution of nidovirus endoribonuclease based on the finding that nsp15 from porcine Deltacoronavirus functions as a dimer

Zheng

Shi

Shen

et al. 2018

Journal of Biological Chemistry

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Nidovirus endoribonucleases (NendoUs) include nonstructural protein 15 (nsp15) from coronaviruses and nsp11 from arteriviruses, both of which have been reported to participate in the viral replication process and in the evasion of the host immune system. Results from a previous study of coronaviruses SARS-CoV, HCoV-229E, and MHV nsp15 indicate that it mainly forms a functional hexamer, whereas nsp11 from the arterivirus PRRSV is a dimer. Here, we found that porcine (PDCoV) nsp15 primarily exists as dimers and monomers Biological experiments reveal that a PDCoV nsp15 mutant lacking the first 27 amino acids of the N-terminal domain (Asn-1-Asn-27) forms more monomers and displays decreased enzymatic activity, indicating that this region is important for its dimerization. Moreover, multiple sequence alignments and three-dimensional structural analysis indicated that the C-terminal region (His-251-Val-261) of PDCoV nsp15 is 10 amino acids shorter and forms a shorter loop than that formed by the equivalent sequence (Gln-259-Phe-279) of SARS-CoV nsp15. This result may explain why PDCoV nsp15 failed to form hexamers. We speculate that NendoUs may have originated from XendoU endoribonucleases (XendoUs) forming monomers in eukaryotic cells, that NendoU from arterivirus gained the ability to form dimers, and that the coronavirus variants then evolved the capacity to assemble into hexamers. We further propose that PDCoV nsp15 may be an intermediate in this evolutionary process. Our findings provide a theoretical basis for improving our understanding of NendoU evolution and offer useful clues for designing drugs and vaccines against nidoviruses.

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Functional determinants of protein assembly into homomeric complexes

Cited by 59 publications

References 60 publications

Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors

Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors

The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs

Insight into the evolution of nidovirus endoribonuclease based on the finding that nsp15 from porcine Deltacoronavirus functions as a dimer

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