Conformational Plasticity in Human Heme-Based Dioxygenases

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

Microorganisms ◽

10.3390/microorganisms9050956 ◽

2021 ◽

Vol 9 (5) ◽

pp. 956

Author(s):

Cihan Makbul ◽

Vladimir Khayenko ◽

Hans Michael Maric ◽

Bettina Böttcher

Keyword(s):

Hepatitis B ◽

Core Protein ◽

Peptide Binding ◽

Surface Proteins ◽

Binding Motif ◽

Virus Particles ◽

Enveloped Virus ◽

Conformational Plasticity ◽

Viral Maturation ◽

Hepatitis B Core Protein

Hepatitis B virus is a major human pathogen, which forms enveloped virus particles. During viral maturation, membrane-bound hepatitis B surface proteins package hepatitis B core protein capsids. This process is intercepted by certain peptides with an “LLGRMKG” motif that binds to the capsids at the tips of dimeric spikes. With microcalorimetry, electron cryo microscopy and peptide microarray-based screens, we have characterized the structural and thermodynamic properties of peptide binding to hepatitis B core protein capsids with different secretion phenotypes. The peptide “GSLLGRMKGA” binds weakly to hepatitis B core protein capsids and mutant capsids with a premature (F97L) or low-secretion phenotype (L60V and P5T). With electron cryo microscopy, we provide novel structures for L60V and P5T and demonstrate that binding occurs at the tips of the spikes at the dimer interface, splaying the helices apart independent of the secretion phenotype. Peptide array screening identifies “SLLGRM” as the core binding motif. This shortened motif binds only to one of the two spikes in the asymmetric unit of the capsid and induces a much smaller conformational change. Altogether, these comprehensive studies suggest that the tips of the spikes act as an autonomous binding platform that is unaffected by mutations that affect secretion phenotypes.

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Conformational Plasticity of the Gerstmann–Sträussler–Scheinker Disease Peptide as Indicated by Its Multiple Aggregation Pathways

Journal of Molecular Biology ◽

10.1016/j.jmb.2008.06.063 ◽

2008 ◽

Vol 381 (5) ◽

pp. 1349-1361 ◽

Cited By ~ 45

Author(s):

Antonino Natalello ◽

Valery V. Prokorov ◽

Fabrizio Tagliavini ◽

Michela Morbin ◽

Gianluigi Forloni ◽

...

Keyword(s):

Conformational Plasticity

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Conformational plasticity of the Ebola virus matrix protein

Protein Science ◽

10.1002/pro.2541 ◽

2014 ◽

Vol 23 (11) ◽

pp. 1519-1527 ◽

Cited By ~ 24

Author(s):

Jens Radzimanowski ◽

Gregory Effantin ◽

Winfried Weissenhorn

Keyword(s):

Matrix Protein ◽

Ebola Virus ◽

Conformational Plasticity

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Structural Basis for Dodecameric Assembly States and Conformational Plasticity of the Full-Length AAA+ ATPases Rvb1·Rvb2

Structure ◽

10.1016/j.str.2014.12.015 ◽

2015 ◽

Vol 23 (3) ◽

pp. 483-495 ◽

Cited By ~ 30

Author(s):

Kristina Lakomek ◽

Gabriele Stoehr ◽

Alessandro Tosi ◽

Monika Schmailzl ◽

Karl-Peter Hopfner

Keyword(s):

Full Length ◽

Structural Basis ◽

Conformational Plasticity ◽

Aaa Atpases

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Structural insights into the conformational plasticity of the full-length trimeric HIV-1 envelope glycoprotein precursor

10.1101/288472 ◽

2018 ◽

Author(s):

Shijian Zhang ◽

Wei Li Wang ◽

Shuobing Chen ◽

Maolin Lu ◽

Eden P. Go ◽

...

Keyword(s):

Viral Entry ◽

Envelope Glycoprotein ◽

Structural Data ◽

Full Length ◽

Heptad Repeat ◽

Structural Basis ◽

Glycoprotein Precursor ◽

Helix Bundle ◽

Conformational Plasticity ◽

Hiv 1

SummaryThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer mediates viral entry into cells and is the major target for the host antibody response. In infected cells, the mature Env [(gp120/gp41)3] is produced by cleavage of a trimeric gp160 precursor. Proteolytic cleavage decreases Env conformational flexibility, allowing the mature Env to resist antibody binding to conserved elements. The conformational plasticity of the Env precursor skews the humoral immune response towards the elicitation of ineffectual antibodies, contributing to HIV-1 persistence in the infected host. The structural basis for the plasticity of the Env precursor remains elusive. Here we use cryo-electron microscopy to visualize two coexisting conformational states of the full-length Env precursor at nominal resolutions of 5.5 and 8.0 Å. The State-P2 conformation features a three-helix bundle of the gp41 heptad repeat region in the core, but has disordered membrane-interactive regions. State-P1 trimers lack the three-helix bundle and instead retain ordered transmembrane and membrane-proximal external regions embracing a central cavity. Our structural data shed light on the unusual plasticity of the Env precursor and provide new clues to Env immunogen discovery.

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Modulating the Pro-apoptotic Activity of Cytochrome c at a Biomimetic Electrified Interface

10.26434/chemrxiv.14229605.v1 ◽

2021 ◽

Author(s):

Alonso Gamero-Quijano ◽

Shayon Bhattacharya ◽

Pierre-André Cazade ◽

Andrés F. Molina-Osorio ◽

Cillian Beecher ◽

...

Keyword(s):

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Inner Mitochondrial Membrane ◽

Foetal Development ◽

Drug Molecules ◽

Electrified Interface ◽

Conformational Plasticity ◽

Apoptotic Activity

Programmed cell death via apoptosis is a natural defence against excessive cell division, crucial at all stages of life from foetal development to maintenance of homeostasis and elimination of precancerous and senescent cells. Here we demonstrate an electrified liquid bio-interface that replicates the molecular machinery of the inner mitochondrial membrane at the onset of apoptosis. By mimicking in vivo cytochrome c (Cyt c) interactions with cell membranes, our platform allows us to modulate the conformational plasticity of the protein by simply varying the electrochemical environment at an aqueous|organic interface. As proof-of-concept, we use our electrified liquid bio-interface to identify drug molecules that can potentially downregulate Cyt c and protect against uncontrolled neuronal cell death in Alzheimer’s disease and other neurodegenerative disorders.

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Iron-binding activity in yeast frataxin entails a trade off with stability in the α1/β1 acidic ridge region

Biochemical Journal ◽

10.1042/bj20091612 ◽

2010 ◽

Vol 426 (2) ◽

pp. 197-203 ◽

Cited By ~ 27

Author(s):

Ana R. Correia ◽

Tao Wang ◽

Elizabeth A. Craig ◽

Cláudio M. Gomes

Keyword(s):

Binding Capacity ◽

Mitochondrial Protein ◽

Thermal Stabilization ◽

Autosomal Recessive Disorder ◽

Binding Activity ◽

Iron Binding ◽

Functional Regions ◽

Conformational Plasticity ◽

Iron Binding Capacity ◽

Β Sheet

Frataxin is a highly conserved mitochondrial protein whose deficiency in humans results in Friedreich's ataxia (FRDA), an autosomal recessive disorder characterized by progressive ataxia and cardiomyopathy. Although its cellular function is still not fully clear, the fact that frataxin plays a crucial role in Fe–S assembly on the scaffold protein Isu is well accepted. In the present paper, we report the characterization of eight frataxin variants having alterations on two putative functional regions: the α1/β1 acidic ridge and the conserved β-sheet surface. We report that frataxin iron-binding capacity is quite robust: even when five of the most conserved residues from the putative iron-binding region are altered, at least two iron atoms per monomer can be bound, although with decreased affinity. Furthermore, we conclude that the acidic ridge is designed to favour function over stability. The negative charges have a functional role, but at the same time significantly impair frataxin's stability. Removing five of those charges results in a thermal stabilization of ~24 °C and reduces the inherent conformational plasticity. Alterations on the conserved β-sheet residues have only a modest impact on the protein stability, highlighting the functional importance of residues 122–124.

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