BPPred: A Web‐based computational tool for predicting biophysical parameters of proteins

Geierhaas, Christian D.; Nickson, Adrian A.; Lindorff‐Larsen, Kresten; Clarke, Jane; Vendruscolo, Michele

doi:10.1110/ps.062383807

Cited by 60 publications

(59 citation statements)

References 87 publications

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“…Considering that the G B 88 construct contains ϳ10 structured residues more than G A 88, both m DϪN values are consistent with those expected for proteins of this size, according to the BPPred database (31). Hence, the seeming difference in cooperativity, as reflected by the different m DϪN values, can be accounted for by the difference in the number of structured residues between the two proteins.…”

Section: Resultssupporting

confidence: 82%

The Denatured State Dictates the Topology of Two Proteins with Almost Identical Sequence but Different Native Structure and Function

Morrone

McCully

Bryan

et al. 2011

Journal of Biological Chemistry

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The protein folding problem is often studied by comparing the mechanisms of proteins sharing the same structure but different sequence. The recent design of the two proteins G A 88 and G B 88, displaying different structures and functions while sharing 88% sequence identity (49 out of 56 amino acids), allows the unique opportunity for a complementary approach. At which stage of its folding pathway does a protein commit to a given topology? Which residues are crucial in directing folding mechanisms to a given structure? By using a combination of biophysical and computational techniques, we have characterized the folding of both G A 88 and G B 88. We show that, contrary to expectation, G B 88, characterized by a native ␣؉␤ fold, displays in the denatured state a content of native-like helical structure greater than G A 88, which is all-␣ in its native state. Both experiments and simulations indicate that such residual structure may be tuned by changing pH. Thus, despite the high sequence identity, the folding pathways for these two proteins appear to diverge as early as in the denatured state. Our results suggest a mechanism whereby protein topology is committed very early along the folding pathway, being imprinted in the residual structure of the denatured state.

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Section: Resultssupporting

confidence: 82%

The Denatured State Dictates the Topology of Two Proteins with Almost Identical Sequence but Different Native Structure and Function

Morrone

McCully

Bryan

et al. 2011

Journal of Biological Chemistry

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“…S2 B and C). This value is relatively low compared to that expected for a protein of this size, ∼2 kcal mol −1°C−1 (32,33), suggesting that the reduced apo monomer may be less structured than a typical globular protein.…”

Section: Resultsmentioning

confidence: 65%

Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS

Vassall¹,

Stubbs²,

Primmer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

100

145

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Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS), where aggregation of Cu/Zn superoxide dismutase (SOD1) is implicated in causing neurodegeneration. Recent studies have suggested that destabilization and aggregation of the most immature form of SOD1, the disulfide-reduced, unmetallated (apo) protein is particularly important in causing ALS. We report herein in depth analyses of the effects of chemically and structurally diverse ALS-associated mutations on the stability and aggregation of reduced apo SOD1. In contrast with previous studies, we find that various reduced apo SOD1 mutants undergo highly reversible thermal denaturation with little aggregation, enabling quantitative thermodynamic stability analyses. In the absence of ALS-associated mutations, reduced apo SOD1 is marginally stable but predominantly folded. Mutations generally result in slight decreases to substantial increases in the fraction of unfolded protein. Calorimetry, ultracentrifugation, and light scattering show that all mutations enhance aggregation propensity, with the effects varying widely, from subtle increases in most cases, to pronounced formation of 40–100 nm soluble aggregates by A4V, a mutation that is associated with particularly short disease duration. Interestingly, although there is a correlation between observed aggregation and stability, there is minimal to no correlation between observed aggregation, predicted aggregation propensity, and disease characteristics. These findings suggest that reduced apo SOD1 does not play a dominant role in modulating disease. Rather, additional and/or multiple forms of SOD1 and additional biophysical and biological factors are needed to account for the toxicity of mutant SOD1 in ALS.

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“…In the study of monomeric proteinfolding, the position of the TS along one reaction coordinate can be estimated using the denaturant dependence of folding and unfolding rate constants (40). A similar approach was applied to the folding and binding of PUMA-MCL-1.…”

Section: Resultsmentioning

confidence: 99%

Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein

Rogers

Oleinikovas

Shammas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

155

181

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Protein-protein interactions are at the heart of regulatory and signaling processes in the cell. In many interactions, one or both proteins are disordered before association. However, this disorder in the unbound state does not prevent many of these proteins folding to a well-defined, ordered structure in the bound state. Here we examine a typical system, where a small disordered protein (PUMA, p53 upregulated modulator of apoptosis) folds to an α-helix when bound to a groove on the surface of a folded protein (MCL-1, induced myeloid leukemia cell differentiation protein). We follow the association of these proteins using rapid-mixing stopped flow, and examine how the kinetic behavior is perturbed by denaturant and carefully chosen mutations. We demonstrate the utility of methods developed for the study of monomeric protein folding, including β-Tanford values, Leffler α, Φ-value analysis, and coarse-grained simulations, and propose a self-consistent mechanism for binding. Folding of the disordered protein before binding does not appear to be required and few, if any, specific interactions are required to commit to association. The majority of PUMA folding occurs after the transition state, in the presence of MCL-1. We also examine the role of the side chains of folded MCL-1 that make up the binding groove and find that many favor equilibrium binding but, surprisingly, inhibit the association process.Protein folding | stopped flow | coarse-grained simulation | protein-protein interactions | BCL-2

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BPPred: A Web‐based computational tool for predicting biophysical parameters of proteins

Cited by 60 publications

References 87 publications

The Denatured State Dictates the Topology of Two Proteins with Almost Identical Sequence but Different Native Structure and Function

The Denatured State Dictates the Topology of Two Proteins with Almost Identical Sequence but Different Native Structure and Function

Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS

Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein

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