Intra-Helical Salt Bridge Contribution to Membrane Protein Insertion

Duart, Gerard; Lamb, John; Ortiz-Mateu, Juan; Elofsson, Arne; Mingarro, Ismael

doi:10.1016/j.jmb.2022.167467

Cited by 4 publications

(11 citation statements)

References 57 publications

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“…Salt bridges are also found to contribute towards protein stabilization [159]. They are found to play a role in the folding of globular proteins, and may contribute towards membrane protein stability, conformational specificity, and the positioning of critical functional groups [160,161]. Another key characteristic within the complexes is the smaller proportion of aggregation-prone residues, as aggregation may lead to the reduction of production yield and final product activities and may trigger unpredictable immune responses in patients [162,163].…”

Section: Discussionmentioning

confidence: 99%

“…These interactions are an important factor for binding affinity [168]. Hydrogen bonds and salt bridges are classified mainly as electrostatic interactions [158,160]. This may have contributed towards the significant electrostatic energy contributions.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Multi-epitope vaccine candidates based on mycobacterial membrane protein large (MmpL) proteins against Mycobacterium ulcerans

Ishwarlall,

Adeleke,

Maharaj

et al. 2023

Open Biol.

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Buruli ulcer (BU) is a neglected tropical disease. It is caused by the bacterium Mycobacterium ulcerans and is characterized by skin lesions. Several studies were performed testing the Bacillus Calmette-Guérin (BCG) vaccine in human and animal models and M. ulcerans- specific vaccines in animal models. However, there are currently no clinically accepted vaccines to prevent M. ulcerans infection. The aim of this study was to identify T-cell and B-cell epitopes from the mycobacterial membrane protein large (MmpL) proteins of M. ulcerans. These epitopes were analysed for properties including antigenicity, immunogenicity, non-allergenicity, non-toxicity, population coverage and the potential to induce cytokines. The final 8 CD8 + , 12 CD4 + T-cell and 5 B-cell epitopes were antigenic, non-allergenic and non-toxic. The estimated global population coverage of the CD8 + and CD4 + epitopes was 97.71%. These epitopes were used to construct five multi-epitope vaccine constructs with different adjuvants and linker combinations. The constructs underwent further structural analyses and refinement. The constructs were then docked with Toll-like receptors. Three of the successfully docked complexes were structurally analysed. Two of the docked complexes successfully underwent molecular dynamics simulations (MDS) and post-MDS analysis. The complexes generated were found to be stable. However, experimental validation of the complexes is required.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Multi-epitope vaccine candidates based on mycobacterial membrane protein large (MmpL) proteins against Mycobacterium ulcerans

Ishwarlall,

Adeleke,

Maharaj

et al. 2023

Open Biol.

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“…A couple of mechanisms have been suggested before to aid the insertion of charged amino acids into hydrophobic membrane cores: The formation of water defects where water molecules surround polar and charged residues inside the membrane Ulmschneider (2017); Wang et al (2014); Allolio et al (2016); Dorairaj and Allen (2007); Bonhenry et al (2013); Li et al (2013), the bending of lipids enabling polar and charged headgroups (e.g. phosphates) to stabilize residues of opposing charge Allolio et al (2016); Dorairaj and Allen (2007); Li et al (2013), salt-bridge formation between residues of opposing charges Duart et al (2022); Mbaye et al (2019); Chin and von Heijne (2000); Donald et al (2011), "piggyback" where one charged residue drags water into the membrane and thereby paves the way for membrane insertion of further charged residues at hardly any extra cost MacCallum et al (2007MacCallum et al ( , 2008, with arginine and its guanidinium cation presenting a special case titled "arginine magic" Vazdar et al (2018); Allolio et al (2016); Moon and Fleming (2011), as well as mediating effects of the protein surroundings that provide charge shielding and stabilization Bosshart et al (2012); Vögele et al (2019); Altrichter et al (2017); Moon and Fleming (2011); Cymer et al (2015); van Dalen and de Kruijff (2004).…”

Section: Introductionmentioning

confidence: 99%

Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3

Korn

Pluháčková

2022

Front. Cell Dev. Biol.

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Gasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of smaller to larger oligomers and reshaping from slits to rings could be documented, the initiation of the gasdermin pore formation remains a mystery. In one hypothesis, gasdermin monomers insert into membranes before associating into oligomeric pores. In the other hypothesis, gasdermin oligomers preassemble on the membrane surface prior to membrane insertion. Here, by studying the behavior of monomeric membrane-inserted gasdermin-A3 (GSDMA3), we unveil that a monomeric gasdermin prefers the membrane-adsorbed over the membrane-inserted state. Our results thus support the hypothesis of oligomers preassembling on the membrane surface before membrane penetration. At the same time, our simulations of small membrane-inserted arcs of GSDMA3 suggest that the inserting oligomer can be small and does not have to comprise a full ring of approximately 26–30 subunits. Moreover, our simulations have revealed an astonishingly large impact of salt-bridge formation and protein surroundings on the transmembrane passage of charged residues, reducing the energetic cost by up to 53% as compared to their free forms. The here observed free energy barrier of mere 5.6 kcal/mol for the membrane insertion of monomeric GSDMA3 explains the surprising ability of gasdermins to spontaneously self-insert into cellular membranes.

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“…En ambos casos, se trata de hélices separadas por un enlace peptídico entre dos residuos cargados contiguos (resaltado en azul), según la predicción realizada por la base de datos. Este enlace podría explicar en parte por qué estos péptidos no se deberían insertar en la membrana, puesto que la mayoría de herramientas de predicción de topología de membrana modernas consideran que la presencia de aminoácidos cargados supone una penalización en la energía libre prevista de la inserción (Duart et al, 2022). Sin embargo, solo viendo esta predicción de estructura no estaba claro el tipo de relación que podrían tener el péptido DVL1 y DVL11 con la membrana plasmática.…”

Section: Antecedentes Y Resultados Previosunclassified

Los péptidos DEVIL: estudio de su papel en el control de la proliferación celular y la morfogénesis de las plantas

Alarcia García

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Antes de entrar en materia, me gustaría dedicar unas palabras a todas las personas, o al menos intentarlo, gracias a las cuales ha sido posible realizar y sobre todo terminar esta tesis.En primer lugar, agradecer a Cristina, mi directora, por permitirme formar parte de su equipo y que confió en mi este GRAN trabajo que han sido los DEVIL. Gracias por intentar guiarme de la mejor manera, confiar en mi trabajo y darme la oportunidad de adentrarme en el camino de la ciencia. También agradecer al resto de mis compañeros tanto de mi laboratorio como del de Paco, que tan bien siempre me ha acogido: Irene, Paz, Francisca, Carolina, Vicente, Ludo, Edu, Patri, Ana B, Majo… gracias por la ayuda y acompañamiento dentro del labo pero también fuera en forma de merecidas reuniones alrededor de una mesa llena de cervezas.Como no acordarme de todas las personas con las que comencé estas andadas y que se han convertido en grandes amigos y sobre todo en mi familia aquí en Valencia: Vero, Clara, Pra, Rubén, M. Ángeles, Flo, Marina y Roser, gracias por hacer que mi vida en esta ciudad haya sido tan buena y divertida.Pero sobre todo me gustaría dar las GRACIAS a mi familia, que tanto me ha apoyado y ha confiado en mi en este camino de altibajos, sin ellos esto no sería posible. Gracias por estar seguros de que lo iba a conseguir haciendo que mi proyecto sea también y muy merecidamente vuestro. Aun estando lejos de casa, os he sentido aquí conmigo, apoyándome incluso sin palabras o sin preguntar cuando notabais que no era el momento. Y como no, mi último agradecimiento a Sergio que, aunque llegaste a mitad del camino, tan fácil me lo has hecho, sobre todo en la recta final en la que más complicado ha podido ser todo, confiando en mí, tu 100tifica, tan ciegamente. Gracias por ser mi confidente, mi compañero fiel, de risas, amor y llanto.En definitiva, gracias a todos aquellos que, aunque igual no haya mencionado directamente, me habéis hecho crecer, no solo como científica sino también como persona. Tras ocho años aquí en Valencia, cuando llegué a empezar el máster y me inicié en este trabajo, han sido muchas las personas que me habéis acompañado, así que gracias. RESÚMENES RESÚMENES v RESUMENLos péptidos DEVIL/ROTUNDIFOLIA (DVL/RTFL) constituyen una familia de péptidos de pequeño tamaño codificados por la familia génica DEVIL/ROTUNDIFOLIA (DVL/RTFL) de 24 miembros en Arabidopsis thaliana. Estos genes fueron caracterizados por los fenotipos que confiere su sobreexpresión, que provoca cambios pronunciados en la morfología de la planta con hojas de roseta más redondeadas, plantas de menor estatura, peciolos cortos e inflorescencias compactas. Además, estos fenotipos afectan de un modo fascinante a la morfología de los frutos, que varía según qué miembro de la familia se sobreexprese, demostrando tener un papel en el desarrollo de múltiples órganos de la planta.

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Intra-Helical Salt Bridge Contribution to Membrane Protein Insertion

Cited by 4 publications

References 57 publications

Multi-epitope vaccine candidates based on mycobacterial membrane protein large (MmpL) proteins against Mycobacterium ulcerans

Multi-epitope vaccine candidates based on mycobacterial membrane protein large (MmpL) proteins against Mycobacterium ulcerans

Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3

Los péptidos DEVIL: estudio de su papel en el control de la proliferación celular y la morfogénesis de las plantas

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