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Structural, Functional and Folding Strategies of Oligomeric Proteins

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 11693

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Special Issue Editors

Dr. Giampiero Mei

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Guest Editor

Dipartimento di Medicina Sperimentale, Università di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
Interests: protein folding; protein-membrane interaction; protein structure-to-function relationship; protein fluorescence
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Dr. Luisa Di Paola

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Co-Guest Editor

Faculty of Engineering, Università Campus Biomedico di Roma, Via Alvaro del Portillo, 21-00128 Rome, Italy
Interests: medicinal chemistry; natural products; drug discovery & design; computational biology; allosteric drugs

Special Issue Information

Dear Colleagues,

Most of the proteins and enzymes that govern the life of cells exist as oligomers, suggesting that forming supramolecular aggregates provide important evolutionary advantages. Multisubunit proteins play a key role in the main metabolic pathways, speeding up reactions and exerting fine-tuned control of the complex biochemical processes that take place in all living organisms. Such tasks are accomplished through tight cooperation among monomers, which give rise to new structural and functional properties, which are unachievable in a single chain protein. Another explanation for the widespread presence of oligomers in nature comes from thermodynamic studies. Kinetic and equilibrium folding/unfolding measurements have, in fact, demonstrated that the quaternary structure generally increases single monomers’ stability, being very often the main driving force of their folding pathway. On the other hand, several kinds of network analysis have demonstrated how local perturbation in one subunit can be transmitted to the others through a few contacts localized at the interface(s) that separate them, thus inducing researchers of different fields to focus their interest on the structural characterization of such interfaces. Such a task is important, not only to better understand the structural and functional properties of these macromolecules but also because it may shed new light on the more general protein–protein interaction process, a physical event that fundamentally encompasses most human body physiological features, including muscles contraction, signal transmission, and molecular recognition, to mention a few. Despite the structural and functional advantages provided by multisubunit assembly and cooperation, in some cases monomers association might yield wrong folded intermediates that can lead to aggregation and severe pathologies.

This Special Issue, “Structural, Functional, and Folding Strategies of Oligomeric Proteins” will collect papers in this research field dealing with one of the following topics: a) folding pathways in multisubunit proteins; b) cooperative effects in multimeric structures; c) structural features of intersubunit interfaces; d) contact networks and symmetry analysis of oligomers; and e) the wrong face of oligomerization: aggregation and disease.

Prof. Giampiero Mei
Dr. Luisa Di Paola
Guest Editors

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Keywords

oligomers folding
protein contact network
protein aggregation
oligomers hierarchy
misfolding
protein–protein interface

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Published Papers (4 papers)

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Research

24 pages, 5586 KiB

Open AccessArticle

Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations

by Julie Ledoux, Alain Trouvé and Luba Tchertanov

Int. J. Mol. Sci. 2021, 22(14), 7375; https://doi.org/10.3390/ijms22147375 - 9 Jul 2021

Cited by 6 | Viewed by 2354

Abstract

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 3₁₀-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects. Full article

(This article belongs to the Special Issue Structural, Functional and Folding Strategies of Oligomeric Proteins)

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15 pages, 3942 KiB

Open AccessArticle

The Odd Faces of Oligomers: The Case of TRAF2-C, A Trimeric C-Terminal Domain of TNF Receptor-Associated Factor

by Almerinda Di Venere, Eleonora Nicolai, Velia Minicozzi, Anna Maria Caccuri, Luisa Di Paola and Giampiero Mei

Int. J. Mol. Sci. 2021, 22(11), 5871; https://doi.org/10.3390/ijms22115871 - 30 May 2021

Cited by 7 | Viewed by 2784

Abstract

TNF Receptor Associated Factor 2 (TRAF2) is a trimeric protein that belongs to the TNF receptor associated factor family (TRAFs). The TRAF2 oligomeric state is crucial for receptor binding and for its interaction with other proteins involved in the TNFR signaling. The monomer-trimer equilibrium of a C- terminal domain truncated form of TRAF2 (TRAF2-C), plays also a relevant role in binding the membrane, causing inward vesiculation. In this study, we have investigated the conformational dynamics of TRAF2-C through circular dichroism, fluorescence, and dynamic light scattering, performing temperature-dependent measurements. The data indicate that the protein retains its oligomeric state and most of its secondary structure, while displaying a significative increase in the heterogeneity of the tyrosines signal, increasing the temperature from ≈15 to ≈35 °C. The peculiar crowding of tyrosine residues (12 out of 18) at the three subunit interfaces and the strong dependence on the trimer concentration indicate that such conformational changes mainly involve the contact areas between each pair of monomers, affecting the oligomeric state. Molecular dynamic simulations in this temperature range suggest that the interfaces heterogeneity is an intrinsic property of the trimer that arises from the continuous, asymmetric approaching and distancing of its subunits. Such dynamics affect the results of molecular docking on the external protein surface using receptor peptides, indicating that the TRAF2-receptor interaction in the solution might not involve three subunits at the same time, as suggested by the static analysis obtainable from the crystal structure. These findings shed new light on the role that the TRAF2 oligomeric state might have in regulating the protein binding activity in vivo. Full article

(This article belongs to the Special Issue Structural, Functional and Folding Strategies of Oligomeric Proteins)

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18 pages, 32313 KiB

Open AccessArticle

Conformational Heterogeneity and Cooperative Effects of Mammalian ALOX15

by Igor Ivanov, Alejandro Cruz, Alexander Zhuravlev, Almerinda Di Venere, Eleonora Nicolai, Sabine Stehling, José M. Lluch, Àngels González-Lafont and Hartmut Kuhn

Int. J. Mol. Sci. 2021, 22(6), 3285; https://doi.org/10.3390/ijms22063285 - 23 Mar 2021

Cited by 6 | Viewed by 2728

Abstract

Arachidonic acid lipoxygenases (ALOXs) have been suggested to function as monomeric enzymes, but more recent data on rabbit ALOX15 indicated that there is a dynamic monomer-dimer equilibrium in aqueous solution. In the presence of an active site ligand (the ALOX15 inhibitor RS7) rabbit ALOX15 was crystalized as heterodimer and the X-ray coordinates of the two monomers within the dimer exhibit subtle structural differences. Using native polyacrylamide electrophoresis, we here observed that highly purified and predominantly monomeric rabbit ALOX15 and human ALOX15B are present in two conformers with distinct electrophoretic mobilities. In silico docking studies, molecular dynamics simulations, site directed mutagenesis experiments and kinetic measurements suggested that in aqueous solutions the two enzymes exhibit motional flexibility, which may impact the enzymatic properties. Full article

(This article belongs to the Special Issue Structural, Functional and Folding Strategies of Oligomeric Proteins)

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23 pages, 2230 KiB

Open AccessArticle

The Histidine Phosphocarrier Kinase/Phosphorylase from Bacillus Subtilis Is an Oligomer in Solution with a High Thermal Stability

by José L. Neira, Ana Cámara-Artigas, José Ginés Hernández-Cifre and María Grazia Ortore

Int. J. Mol. Sci. 2021, 22(6), 3231; https://doi.org/10.3390/ijms22063231 - 22 Mar 2021

Cited by 4 | Viewed by 2678

Abstract

The histidine phosphocarrier protein (HPr) kinase/phosphorylase (HPrK/P) modulates the phosphorylation state of the HPr protein, and it is involved in the use of carbon sources by Gram-positive bacteria. Its X-ray structure, as concluded from crystals of proteins from several species, is a hexamer; however, there are no studies about its conformational stability, and how its structure is modified by the pH. We have embarked on the conformational characterization of HPrK/P of Bacillus subtilis (bsHPrK/P) in solution by using several spectroscopic (namely, fluorescence and circular dichroism (CD)) and biophysical techniques (namely, small-angle X-ray-scattering (SAXS) and dynamic light-scattering (DLS)). bsHPrK/P was mainly a hexamer in solution at pH 7.0, in the presence of phosphate. The protein had a high conformational stability, with an apparent thermal denaturation midpoint of ~70 °C, at pH 7.0, as monitored by fluorescence and CD. The protein was very pH-sensitive, precipitated between pH 3.5 and 6.5; below pH 3.5, it had a molten-globule-like conformation; and it acquired a native-like structure in a narrow pH range (between pH 7.0 and 8.0). Guanidinium hydrochloride (GdmCl) denaturation occurred through an oligomeric intermediate. On the other hand, urea denaturation occurred as a single transition, in the range of concentrations between 1.8 and 18 µM, as detected by far-UV CD and fluorescence. Full article

(This article belongs to the Special Issue Structural, Functional and Folding Strategies of Oligomeric Proteins)

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