Electrostatic Effects in the Folding of the SH3 Domain of the c-Src Tyrosine Kinase: pH-Dependence in 3D-Domain Swapping and Amyloid Formation

Bacarizo, Julio; Martínez‐Rodríguez, Sergio; Martín-García, José M.; Andújar‐Sánchez, Montserrat; Ortiz‐Salmerón, Emilia; Neira, José L.; Cámara-Artigas, A.

doi:10.1371/journal.pone.0113224

Cited by 26 publications

(29 citation statements)

References 77 publications

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“…Thus, the Fyn SH3domain crystal structure contains two molecules in the asymmetric unit with different conformations, the same as the crystal structure of the c-Src SH3 domain. Each molecule has a different conformation: chain B contains the same water molecules w1 and w2 as found in the Fyn SH3-VSL12 complex, while chain A does not (Bacarizo et al, 2014). Additionally, Leu101 (Leu100 in c-Src SH3) shows different conformers in each chain and we have proposed a relevant role of this residue in the conformational changes that take place to accommodate the binding of PRMs in the two available orientations (Bacarizo et al, 2015).…”

Section: Comparison Of the Hydration Spots Present In The Fyn Sh3 Commentioning

confidence: 78%

The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase

et al. 2016

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Interactions of proline-rich motifs with SH3 domains are present in signal transduction and other important cell processes. Analysis of structural and thermodynamic data suggest a relevant role of water molecules in these protein-protein interactions. To determine whether or not the SH3 domain of the Fyn tyrosine kinase shows the same behaviour, the crystal structures of its complexes with two high-affinity synthetic peptides, VSL12 and APP12, which are class I and II peptides, respectively, have been solved. In the class I complexes two water molecules were found at the binding interface that were not present in the class II complexes. The structures suggest a role of these water molecules in facilitating conformational changes in the SH3 domain to allow the binding of the class I or II peptides. In the third binding pocket these changes modify the cation-π and salt-bridge interactions that determine the affinity of the binding. Comparison of the water molecules involved in the binding of the peptides with previous reported hydration spots suggests a different pattern for the SH3 domains of the Src tyrosine kinase family.

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Section: Comparison Of the Hydration Spots Present In The Fyn Sh3 Commentioning

confidence: 78%

The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase

et al. 2016

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“…To elucidate the mechanism we computed the underlying FES of domain swapping in a single domain globular protein, cSrc-SH3, which is found to form intertwined domain swapped dimers. 46,51 We used coarse-grained SOP-SC model of the Q128E mutant of the dimeric crystal structure 51 (PDB ID: 3FJ5) as a reference system ( Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Cosolvent Effects on the Growth of Protein Aggregates Formed by a Single Domain Globular Protein and an Intrinsically Disordered Protein

Mondal

Reddy

2018

Preprint

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Cosolvents modulate the stability of protein conformations and exhibit contrasting effects on the kinetics of aggregation by globular proteins and intrinsically disordered proteins (IDPs). The growth of ordered protein aggregates, after the initial nucleation step is believed to proceed through a dock-lock mechanism. We have studied the effect of two denaturants (guanidinium chloride (GdmCl) and urea) and four protective osmolytes (trimethylamine N-oxide (TMAO), sucrose, sarcosine, and sorbitol) on the free energy surface (FES) of the dock-lock growth step of protein aggregation using a coarse-grained protein model and metadynamics simulations. We have used the proteins cSrc-SH3 and Aβ 9−40 as model systems representing globular proteins and IDPs, respectively. The effect of cosolvents on protein conformations is taken into account using the molecular transfer model (MTM). The computed FES shows that protective osmolytes stabilize the compact aggregates, while denaturants destabilize them for both cSrc-SH3 and Aβ 9−40 . However, protective osmolytes increase the effective energy barrier for the multi-step domain swapped dimerization of cSrc-SH3, which is critical to the growth of protein aggregates by globular proteins, thus slowing down overall aggregation rate. Contrastingly, denaturants decrease the effective barrier height for cSrc-SH3 dimerization, and hence enhances the aggregation rate in globular proteins.The simulations further show that cSrc-SH3 monomers unfold before dimerization and the barrier to monomer unfolding regulates the effective rate of agrgegation. In the case of IDP, Aβ 9−40 , protective osmolytes decrease and denaturants increase the effective barriers in the dock-lock mechanism of fibril growth, leading to faster and slower growth kinetics, respectively.

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“…The above results showed that promiscuous binding of peptide molecule can be effectively ameliorated by rational design. Based on various public crystallographic data, [33][34][35][36][37][38] the SH3 domain has been thoroughly researched and broadly recognized as one of the best available systems for the examination of ligand-protein interactions. For example, Larson et al constructed a diverse alignment of SH3 domain sequences.…”

Section: Implication Of the Current Resultsmentioning

confidence: 99%

Optimizing the Amino Acid Sequences of Peptides and Improving Their Specificity of Binding to SH3 Domains of Target Proteins

Ren¹,

Wang²,

Li³

2017

IJPER

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Introduction: It is always a crucial challenge in biotechnology to avoid promiscuous binding between an anticancer peptide and multiple SH3 domains, thus reducing potential toxic effects. In spite of a great deal of experimental efforts, the association between amino acid sequence and binding specificity of peptide remained largely unknown. Aim: The purpose of this study was to optimize the amino acid sequence of peptide ligands and render high specificity towards designated therapeutic targets. Results: By exploring peptide ligands in MINT database and utilizing SH3PepInt tool for in silico peptide-target binding, here we investigated how the amino acid sequence of a peptide determined its specificity of binding to the SH3 domain of c-Src protein. We found that the 5

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Electrostatic Effects in the Folding of the SH3 Domain of the c-Src Tyrosine Kinase: pH-Dependence in 3D-Domain Swapping and Amyloid Formation

Cited by 26 publications

References 77 publications

The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase

The role of water molecules in the binding of class I and II peptides to the SH3 domain of the Fyn tyrosine kinase

Cosolvent Effects on the Growth of Protein Aggregates Formed by a Single Domain Globular Protein and an Intrinsically Disordered Protein

Optimizing the Amino Acid Sequences of Peptides and Improving Their Specificity of Binding to SH3 Domains of Target Proteins

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