Asymmetric perturbations of signalling oligomers

Maksay, Gábor; Tőke, Orsolya

doi:10.1016/j.pbiomolbio.2014.03.001

“…Thus, we must be cautious interpreting enrichments in this group, as most quaternary structures are likely to be erroneous. Despite this, it is interesting to note the most significantly enriched functional term for these complexes is “ signal transducer activity ” (3.44-fold enrichment, P = 5 × 10 −6 ; Figure S1), as the prominent role of asymmetry in signalling processes has previously been noted 51, 52 . The second most significantly enriched term is “ DNA binding ” (2.09-fold enrichment, P = 1 × 10 −5 ).…”

Section: Resultsmentioning

confidence: 95%

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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“…Thus, we must be cautious interpreting enrichments in this group, as most quaternary structures are likely to be erroneous. Despite this, it is interesting to note the most significantly enriched functional term for these complexes is "signal transducer activity" (3.44-fold enrichment, P = 5 x 10 -6 ; Figure S1), as the prominent role of asymmetry in signalling processes has previously been noted 48,49 . The second most significantly enriched term is "DNA binding" (2.09-fold enrichment, P = 1 x 10 -5 ).…”

Section: Helical and Asymmetric Homomersmentioning

confidence: 93%

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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“…It is possible that the underlying molecular mechanisms for the regulation of these proteins follows the paradigm that we established here for LapD. Indeed, asymmetry, like that we described for the LapD output domain-LapG complex (Chatterjee et al, 2014), is common among outside-in signaling membrane proteins, including HAMP domain-containing chemotaxis receptors and histidine kinases (Maksay and Tőke, 2014; Milburn et al, 1991; Neiditch et al, 2006; Yeh et al, 1996). For example, binding of the quorum-sensing signal AI-2 to the periplasmic domain of the histidine kinase complex LuxPQ induces asymmetry in its periplasmic domains (Neiditch et al, 2006).…”

Section: Discussionmentioning

confidence: 70%

“…Such a conformation would prime LapD for c-di-GMP binding, which, in turn, would shift the equilibrium to the more extended state, thus preventing autoinhibition. The reason why one protomer appears more dynamic than the other is not well understood, but could indicate anti-cooperative effects in oligomeric receptors analogous to mechanisms described for other bacterial receptors (Maksay and Tőke, 2014). In support of this, we previously showed that only one equivalent of c-di-GMP is required per LapD dimer for maximal LapG binding, and that the high-affinity LapG-binding state of the periplasmic domain of LapD is asymmetric (Chatterjee et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Coincidence detection and bi-directional transmembrane signaling control a bacterial second messenger receptor

Cooley

¹

,

O’Donnell

²

,

Sondermann

³

2016

eLife

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The second messenger c-di-GMP (or cyclic diguanylate) regulates biofilm formation, a physiological adaptation process in bacteria, via a widely conserved signaling node comprising a prototypical transmembrane receptor for c-di-GMP, LapD, and a cognate periplasmic protease, LapG. Previously, we reported a structure-function study of a soluble LapD•LapG complex, which established conformational changes in the receptor that lead to c-di-GMP-dependent protease recruitment (Chatterjee et al., 2014). This work also revealed a basal affinity of c-di-GMP-unbound receptor for LapG, the relevance of which remained enigmatic. Here, we elucidate the structural basis of coincidence detection that relies on both c-di-GMP and LapG binding to LapD for receptor activation. The data indicate that high-affinity for LapG relies on the formation of a receptor dimer-of-dimers, rather than a simple conformational change within dimeric LapD. The proposed mechanism provides a rationale of how external proteins can regulate receptor function and may also apply to c-di-GMP-metabolizing enzymes that are akin to LapD.DOI: http://dx.doi.org/10.7554/eLife.21848.001

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Asymmetric perturbations of signalling oligomers

Cited by 13 publications

References 268 publications

Functional determinants of protein assembly into homomeric complexes

Functional determinants of protein assembly into homomeric complexes

Functional determinants of protein assembly into homomeric complexes

Coincidence detection and bi-directional transmembrane signaling control a bacterial second messenger receptor

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