Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

Jemth, Per; Karlsson, Elin; Vögeli, Beat; Guzovsky, Brenda; Andersson, Eva; Hultqvist, Greta; Dogan, Jakob; Güntert, Peter; Riek, Roland; Celestine, N.

doi:10.1126/sciadv.aau4130

Cited by 44 publications

(69 citation statements)

References 40 publications

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“…The higher NCBD f-values (Table S1 and Figure 2c) measured for the ancestral complex resulted in differences in both the NCBD secondary/tertiary structure and the intermolecular interactions in the TS. In the ancestral TS, the NCBD helix Na3 is totally unfolded (consistent with its lower helicity also in the native state) 31 , while helices Na1 and Na2 are well formed and maintain a native-like relative orientation with numerous Na1-Na2 contacts ( Figure 3c and 3b, box 1). On the other hand, in the human TS, Na1 and Na2 show lower helical content and contacts are less frequent.…”

Section: Experimental Strategymentioning

confidence: 60%

“…On a molecular level, it is intriguing how such multi partner protein domains evolve. In the present study, we have extended our structural studies 31 and investigated the evolution of the binding mechanism using site-directed mutagenesis, f-value analysis and restrained MD simulations to shed light on changes occurring at the molecular level when the low-affinity Cambrian-like NCBD evolved higher affinity for its protein ligand CID.…”

Section: Discussionmentioning

confidence: 99%

“…Previous phylogenetic analyses revealed that while NCBD was present already in the last common ancestor of all bilaterian animals (deuterostomes and protostomes) CID likely emerged later as an interaction domain within the ancestral ACTR/TIF2/SRC protein in the deuterostome lineage (including chordates, echinoderms and hemichordates; Figure 1) 20 . The evolution of the NCBD/CID interaction was previously examined using ancestral sequence reconstruction in combination with several biophysical methods to assess differences in affinity, structure and dynamics between the extant human and ancestral protein complex 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…After the emergence of CID in the ancestral ACTR/TIF2/SRC, NCBD increased its affinity for CID while maintaining the affinity for some of its other binding partners 20 . While the overall structure of the ancestral NCBD/CID complex, which we denote as "Cambrian-like", is similar to the modern high affinity human one, there are several differences on the molecular level ( Figure 1) 21 .…”

Section: Introductionmentioning

confidence: 99%

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Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Karlsson

Paissoni

Erkelens

et al. 2020

Preprint

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Intrinsically disordered protein (IDP) domains often have multiple binding partners. Little is known regarding molecular changes in the binding mechanism when a new interaction evolves from low to high affinity. Here we compared the degree of native contacts in the transition state of the interaction of two IDP domains, low-affinity ancestral and high-affinity human NCBD and CID. We found that the coupled binding and folding mechanism of the domains is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex while more heterogenous transient interactions, including electrostatic, and an increased disorder characterize the human complex. From an evolutionary perspective, adaptation to new binding partners for IDPs may benefit from this ability to exploit multiple alternative transient interactions while retaining the overall pathway.

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Section: Experimental Strategymentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Karlsson

Paissoni

Erkelens

et al. 2020

Preprint

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“…Evolutionary biochemistry, i.e., phylogenetic reconstruction of ancestral sequences followed by expression and experimental characterization of the ancient proteins ( Fig. 2a-b) is a powerful tool for understanding protein function (Hochberg and Thornton 6 2017), including protein-protein interactions (Hultqvist et al 2017;Jemth et al 2018;Wheeler et al 2018). To better understand the evolution and hence function of the PDZ3:CRIPT interaction we reconstructed sequences of ancestral time-matched variants of PDZ3 and CRIPT and compared their binding affinity and stability to PDZ3 and CRIPT from seven extant species.…”

Section: Introductionmentioning

confidence: 99%

Divergent evolution of a protein-protein interaction revealed through ancestral sequence reconstruction and resurrection

Laursen

Čalyševa

Gibson

et al. 2020

Preprint

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The postsynaptic density extends across the postsynaptic dendritic spine with Discs large (DLG) as the most abundant scaffolding protein. DLG dynamically alters the structure of the postsynaptic density, thus controlling the function and distribution of specific receptors at the synapse. PDZ domains make up one of the most abundant protein interaction domain families in animals. One important interaction governing postsynaptic architecture is that between the PDZ3 domain from DLG and cysteinerich interactor of PDZ3 (CRIPT). However, little is know regarding functional evolution of the PDZ3:CRIPT interaction. Here, we subjected PDZ3 and CRIPT to ancestral sequence reconstruction, resurrection and biophysical experiments. We show that the PDZ3:CRIPT interaction is an ancient interaction, which was present in the last common ancestor of Eukaryotes, and that high affinity is maintained in most extant animal phyla. However, affinity is low in nematodes and insects, raising questions about the physiological function of the interaction in species from these animal groups. Our findings demonstrate how an apparently established proteinprotein interaction involved in cellular scaffolding in bilaterians can suddenly be subject to dynamic evolution including possible loss of function.

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High affinity between CREBBP/p300 and NCOA evolved in vertebrates

et al. 2020

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The interaction between the transcriptional coactivators CREBBP/p300 and NCOA is governed by two intrinsically disordered domains called NCBD and CID, respectively. The CID domain emerged within the NCOA protein in deuterostome animals (including vertebrates) after their split from the protostomes (molluscs, worms, and arthropods). However, it has not been clear at which point a high affinity interaction evolved within the deuterostome clade and whether all present‐day deuterostome animals have a high affinity NCBD:CID interaction. We have here expressed and measured affinity for NCBD and CID domains from animal species representing different evolutionary branches of the deuterostome tree. While all vertebrate species have high‐affinity NCBD:CID interactions we found that the interaction in the echinoderm purple sea urchin is of similar affinity as that of the proposed ancestral domains. Our findings demonstrate that the high‐affinity NCBD:CID interaction likely evolved in the vertebrate branch and question whether the interaction between CREBBP/p300 and NCOA is essential in nonvertebrate deuterostomes. The data provide an example of evolution of transcriptional regulation through protein‐domain based inventions.

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Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

Abstract: Structural snapshots characterize six hundred million years of evolution of intrinsically disordered proteins.

Cited by 44 publications

References 40 publications

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Divergent evolution of a protein-protein interaction revealed through ancestral sequence reconstruction and resurrection

High affinity between CREBBP/p300 and NCOA evolved in vertebrates

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