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Structural Determinants of Misfolding in Multidomain Proteins.

Tian P, Best RB - PLoS Comput. Biol. (2016)

Bottom Line: Topology-based simulation models have been used successfully to generate models for these structures with domain-swapped features, fully consistent with the available data.Nonetheless, the results are still fully consistent with the kinetic models previously proposed to explain misfolding, with a specific interpretation of the observed rate coefficients.Finally, we investigate the relation between interdomain linker length and misfolding, and propose a simple alchemical model to predict the propensity for domain-swapped misfolding of multidomain proteins.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Recent single molecule experiments, using either atomic force microscopy (AFM) or Förster resonance energy transfer (FRET) have shown that multidomain proteins containing tandem repeats may form stable misfolded structures. Topology-based simulation models have been used successfully to generate models for these structures with domain-swapped features, fully consistent with the available data. However, it is also known that some multidomain protein folds exhibit no evidence for misfolding, even when adjacent domains have identical sequences. Here we pose the question: what factors influence the propensity of a given fold to undergo domain-swapped misfolding? Using a coarse-grained simulation model, we can reproduce the known propensities of multidomain proteins to form domain-swapped misfolds, where data is available. Contrary to what might be naively expected based on the previously described misfolding mechanism, we find that the extent of misfolding is not determined by the relative folding rates or barrier heights for forming the domains present in the initial intermediates leading to folded or misfolded structures. Instead, it appears that the propensity is more closely related to the relative stability of the domains present in folded and misfolded intermediates. We show that these findings can be rationalized if the folded and misfolded domains are part of the same folding funnel, with commitment to one structure or the other occurring only at a relatively late stage of folding. Nonetheless, the results are still fully consistent with the kinetic models previously proposed to explain misfolding, with a specific interpretation of the observed rate coefficients. Finally, we investigate the relation between interdomain linker length and misfolding, and propose a simple alchemical model to predict the propensity for domain-swapped misfolding of multidomain proteins.

No MeSH data available.


Comparison of domain-swapped misfolds with experimental structures.Selected misfolded dimeric tandems obtained from the simulations (right column) are compared with corresponding experimental structures (solved by crystallography or NMR) of domain-swapped dimers involving two separate protein chains (left column). The proteins are, from top to bottom (a),(b): SH3, (c),(d): SH2, (e),(f): TNfn3 and (g),(h): PDZ domains The PDB accession codes are 1I07, 1FYR, 2RBL and 2OSG respectively.
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pcbi.1004933.g004: Comparison of domain-swapped misfolds with experimental structures.Selected misfolded dimeric tandems obtained from the simulations (right column) are compared with corresponding experimental structures (solved by crystallography or NMR) of domain-swapped dimers involving two separate protein chains (left column). The proteins are, from top to bottom (a),(b): SH3, (c),(d): SH2, (e),(f): TNfn3 and (g),(h): PDZ domains The PDB accession codes are 1I07, 1FYR, 2RBL and 2OSG respectively.

Mentions: The second type of evidence comes from experimental structures of domain-swapped dimers. For several of the proteins, bimolecular domain-swapped structures have been determined experimentally. While no such structures have yet been determined for single-chain tandem dimers, we can compare the misfolded states with the available experimental data. For each experimental example, we are able to find a corresponding misfolded species in our simulation with very similar structure (related by joining the terminis of the two chains in the experimental structures). The domain swapped dimers solved obtained from experiments (Fig 4a, 4c, 4e and 4g) are strikingly similar to the domain swapping dimeric tandem from simulations, which are the domain swapped SH3 domains when K(sequence position after which the central domain begins) = 37 (Fig 4b), SH2 with K = 72 (Fig 4d), TNfn3 with K = 28 (Fig 4f) and PDZ with K = 23 (Fig 4h). Most of these states have relatively high population among all the possible misfolds as observed from the simulations (“Population” in Table 1). While the coverage of possible domain swaps is by no means exhaustive, the observed correspondence gives us confidence that the misfolded states in the simulations are physically plausible.


Structural Determinants of Misfolding in Multidomain Proteins.

Tian P, Best RB - PLoS Comput. Biol. (2016)

Comparison of domain-swapped misfolds with experimental structures.Selected misfolded dimeric tandems obtained from the simulations (right column) are compared with corresponding experimental structures (solved by crystallography or NMR) of domain-swapped dimers involving two separate protein chains (left column). The proteins are, from top to bottom (a),(b): SH3, (c),(d): SH2, (e),(f): TNfn3 and (g),(h): PDZ domains The PDB accession codes are 1I07, 1FYR, 2RBL and 2OSG respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862688&req=5

pcbi.1004933.g004: Comparison of domain-swapped misfolds with experimental structures.Selected misfolded dimeric tandems obtained from the simulations (right column) are compared with corresponding experimental structures (solved by crystallography or NMR) of domain-swapped dimers involving two separate protein chains (left column). The proteins are, from top to bottom (a),(b): SH3, (c),(d): SH2, (e),(f): TNfn3 and (g),(h): PDZ domains The PDB accession codes are 1I07, 1FYR, 2RBL and 2OSG respectively.
Mentions: The second type of evidence comes from experimental structures of domain-swapped dimers. For several of the proteins, bimolecular domain-swapped structures have been determined experimentally. While no such structures have yet been determined for single-chain tandem dimers, we can compare the misfolded states with the available experimental data. For each experimental example, we are able to find a corresponding misfolded species in our simulation with very similar structure (related by joining the terminis of the two chains in the experimental structures). The domain swapped dimers solved obtained from experiments (Fig 4a, 4c, 4e and 4g) are strikingly similar to the domain swapping dimeric tandem from simulations, which are the domain swapped SH3 domains when K(sequence position after which the central domain begins) = 37 (Fig 4b), SH2 with K = 72 (Fig 4d), TNfn3 with K = 28 (Fig 4f) and PDZ with K = 23 (Fig 4h). Most of these states have relatively high population among all the possible misfolds as observed from the simulations (“Population” in Table 1). While the coverage of possible domain swaps is by no means exhaustive, the observed correspondence gives us confidence that the misfolded states in the simulations are physically plausible.

Bottom Line: Topology-based simulation models have been used successfully to generate models for these structures with domain-swapped features, fully consistent with the available data.Nonetheless, the results are still fully consistent with the kinetic models previously proposed to explain misfolding, with a specific interpretation of the observed rate coefficients.Finally, we investigate the relation between interdomain linker length and misfolding, and propose a simple alchemical model to predict the propensity for domain-swapped misfolding of multidomain proteins.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Recent single molecule experiments, using either atomic force microscopy (AFM) or Förster resonance energy transfer (FRET) have shown that multidomain proteins containing tandem repeats may form stable misfolded structures. Topology-based simulation models have been used successfully to generate models for these structures with domain-swapped features, fully consistent with the available data. However, it is also known that some multidomain protein folds exhibit no evidence for misfolding, even when adjacent domains have identical sequences. Here we pose the question: what factors influence the propensity of a given fold to undergo domain-swapped misfolding? Using a coarse-grained simulation model, we can reproduce the known propensities of multidomain proteins to form domain-swapped misfolds, where data is available. Contrary to what might be naively expected based on the previously described misfolding mechanism, we find that the extent of misfolding is not determined by the relative folding rates or barrier heights for forming the domains present in the initial intermediates leading to folded or misfolded structures. Instead, it appears that the propensity is more closely related to the relative stability of the domains present in folded and misfolded intermediates. We show that these findings can be rationalized if the folded and misfolded domains are part of the same folding funnel, with commitment to one structure or the other occurring only at a relatively late stage of folding. Nonetheless, the results are still fully consistent with the kinetic models previously proposed to explain misfolding, with a specific interpretation of the observed rate coefficients. Finally, we investigate the relation between interdomain linker length and misfolding, and propose a simple alchemical model to predict the propensity for domain-swapped misfolding of multidomain proteins.

No MeSH data available.