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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.


Distribution of the “folding nucleus” location  from the tandem dimer simulations (Table 1).The  of the (a) (SH3)2 (b) (SH2)2 (c) (TNfn3)2 and (d) (PDZ)2 are extracted at two different Q on the folding pathway (see individual figure legends for Q values). Note that the Q ∼ 0.5 corresponds to the structure with the first domain fully formed. The spread of contacts in sequence, within a given conformation, also becomes narrower with increasing Q (Fig B of S1 Text).
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pcbi.1004933.g008: Distribution of the “folding nucleus” location from the tandem dimer simulations (Table 1).The of the (a) (SH3)2 (b) (SH2)2 (c) (TNfn3)2 and (d) (PDZ)2 are extracted at two different Q on the folding pathway (see individual figure legends for Q values). Note that the Q ∼ 0.5 corresponds to the structure with the first domain fully formed. The spread of contacts in sequence, within a given conformation, also becomes narrower with increasing Q (Fig B of S1 Text).

Mentions: Further insight into how the above free energy bias influences the outcome of the folding kinetics can be obtained by considering the progressive formation of folded structure. In order to characterize the location of nascent folded structures, we define a new order parameter representing the average position of native contacts along the sequence,ij¯(χ)=1/S(χ)/∑(i,j)∈S(χ)i+j2,(5)where (i, j) is the native or native-like contact formed by the residues i and j in the configuration χ, and S(χ) is the set of all such contacts which are formed in χ. We can locate the position of nascent structure in the sequence by plotting the distributions of for χ drawn from the equilibrium distribution at selected values of the global coordinate Q, defined as the fraction of native contacts in the native dimer structure (i.e. Q = 0.5 corresponds to a single folded or misfolded domain; both native and native-like contacts are counted, and divided by the total number of contacts in the native state). Fig 8 shows that early in folding, at low Q values (shaded histograms in Fig 8), the distribution of is broad, and centered in the middle of the sequence. This implies that folding could potentially begin at many positions along the sequence, with no initial preference for folded or circularly permuted structure. However, as folding proceeds closer to formation of a complete domain, develops two maxima, one in the N-terminal and one in the C-terminal part of the chain, corresponding to native domain formation. The nascent native-like structure thus naturally migrates towards the termini to avoid the free energy penalty of forming a circularly permuted misfolded intermediate.


Structural Determinants of Misfolding in Multidomain Proteins.

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

Distribution of the “folding nucleus” location  from the tandem dimer simulations (Table 1).The  of the (a) (SH3)2 (b) (SH2)2 (c) (TNfn3)2 and (d) (PDZ)2 are extracted at two different Q on the folding pathway (see individual figure legends for Q values). Note that the Q ∼ 0.5 corresponds to the structure with the first domain fully formed. The spread of contacts in sequence, within a given conformation, also becomes narrower with increasing Q (Fig B of S1 Text).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004933.g008: Distribution of the “folding nucleus” location from the tandem dimer simulations (Table 1).The of the (a) (SH3)2 (b) (SH2)2 (c) (TNfn3)2 and (d) (PDZ)2 are extracted at two different Q on the folding pathway (see individual figure legends for Q values). Note that the Q ∼ 0.5 corresponds to the structure with the first domain fully formed. The spread of contacts in sequence, within a given conformation, also becomes narrower with increasing Q (Fig B of S1 Text).
Mentions: Further insight into how the above free energy bias influences the outcome of the folding kinetics can be obtained by considering the progressive formation of folded structure. In order to characterize the location of nascent folded structures, we define a new order parameter representing the average position of native contacts along the sequence,ij¯(χ)=1/S(χ)/∑(i,j)∈S(χ)i+j2,(5)where (i, j) is the native or native-like contact formed by the residues i and j in the configuration χ, and S(χ) is the set of all such contacts which are formed in χ. We can locate the position of nascent structure in the sequence by plotting the distributions of for χ drawn from the equilibrium distribution at selected values of the global coordinate Q, defined as the fraction of native contacts in the native dimer structure (i.e. Q = 0.5 corresponds to a single folded or misfolded domain; both native and native-like contacts are counted, and divided by the total number of contacts in the native state). Fig 8 shows that early in folding, at low Q values (shaded histograms in Fig 8), the distribution of is broad, and centered in the middle of the sequence. This implies that folding could potentially begin at many positions along the sequence, with no initial preference for folded or circularly permuted structure. However, as folding proceeds closer to formation of a complete domain, develops two maxima, one in the N-terminal and one in the C-terminal part of the chain, corresponding to native domain formation. The nascent native-like structure thus naturally migrates towards the termini to avoid the free energy penalty of forming a circularly permuted misfolded intermediate.

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.