scholarly journals Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Lirui Lin ◽  
Haiying Zou ◽  
Wenjin Li ◽  
Li-Yan Xu ◽  
En-Min Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Functional Role ◽  
Catalytic Domain ◽  
Lysyl Oxidase ◽  
Scavenger Receptor ◽  
Redox Potentials ◽  
Catalytic Role

Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes the oxidative deamination ε-amino group of lysine. It is found that LOXL2 is a promotor for the metastasis and invasion of cancer cells. Disulfide bonds are important components in LOXL2, and they play a stabilizing role for protein structure or a functional role for regulating protein bioactivity. The redox potential of disulfide bond is one important property to determine the functional role of disulfide bond. In this study, we have calculated the reduction potential of all the disulfide bonds in LOXL2 by non-equilibrium alchemical simulations. Our results show that seven of seventeen disulfide bonds have high redox potentials between −182 and −298 mV and could have a functional role, viz., Cys573–Cys625, Cys579–Cys695, Cys657–Cys673, and Cys663–Cys685 in the catalytic domain, Cys351–Cys414, Cys464–Cys530, and Cys477–Cys543 in the scavenger receptor cysteine-rich (SRCR) domains. The disulfide bond of Cys351–Cys414 is predicted to play an allosteric function role, which could affect the metastasis and invasion of cancer cells. Other functional bonds have a catalytic role related to enzyme activity. The rest of disulfide bonds are predicted to play a structural role. Our study provides an important insight for the classification of disulfide bonds in LOXL2 and can be utilized for the drug design that targets the cysteine residues in LOXL2.

scholarly journals Role of Conserved Cysteines in the Alphavirus E3 Protein

2008 ◽  
Vol 83 (6) ◽  
pp. 2584-2591 ◽  
Author(s):  
Megan M. Parrott ◽  
Sarah A. Sitarski ◽  
Randy J. Arnold ◽  
Lora K. Picton ◽  
R. Blake Hill ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Viral Entry ◽  
Disulfide Bonds ◽  
Functional Role ◽  
Sindbis Virus ◽  
Virus Assembly ◽  
Wild Type ◽  
Virus Particles ◽  
Extracellular Glycoprotein

ABSTRACT Alphavirus particles are covered by 80 glycoprotein spikes that are essential for viral entry. Spikes consist of the E2 receptor binding protein and the E1 fusion protein. Spike assembly occurs in the endoplasmic reticulum, where E1 associates with pE2, a precursor containing E3 and E2 proteins. E3 is a small, cysteine-rich, extracellular glycoprotein that mediates proper folding of pE2 and its subsequent association with E1. In addition, cleavage of E3 from the assembled spike is required to make the virus particles efficiently fusion competent. We have found that the E3 protein in Sindbis virus contains one disulfide bond between residues Cys19 and Cys25. Replacing either of these two critical cysteines resulted in mutants with attenuated titers. Replacing both cysteines with either alanine or serine resulted in double mutants that were lethal. Insertion of additional cysteines based on E3 proteins from other alphaviruses resulted in either sequential or nested disulfide bond patterns. E3 sequences that formed sequential disulfides yielded virus with near-wild-type titers, while those that contained nested disulfide bonds had attenuated activity. Our data indicate that the role of the cysteine residues in E3 is not primarily structural. We hypothesize that E3 has an enzymatic or functional role in virus assembly, and these possibilities are further discussed.

scholarly journals Functional Role of  -Adrenergic Receptors in the Mitogenic Action of Nicotine on Gastric Cancer Cells

2006 ◽  
Vol 96 (1) ◽  
pp. 21-29 ◽  
Author(s):  
V. Y. Shin ◽  
W. K. K. Wu ◽  
K. M. Chu ◽  
M. W. L. Koo ◽  
H. P. S. Wong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Adrenergic Receptors ◽  
Functional Role ◽  
Gastric Cancer Cells ◽  
Mitogenic Action

The Single Disulfide-Directed β-Hairpin Fold: Role of Disulfide Bond in Folding and Effect of an Additional Disulfide Bond on Stability

2020 ◽  
Vol 73 (4) ◽  
pp. 312
Author(s):  
Balasubramanyam Chittoor ◽  
Bankala Krishnarjuna ◽  
Rodrigo A. V. Morales ◽  
Raymond S. Norton
Keyword(s):  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Solution Structure ◽  
Conformational Stability ◽  
Disulfide Bridge ◽  
Solution Nmr ◽  
Peptide Epitope ◽  
The Core ◽  
Native Fold

Disulfide bonds play a key role in the oxidative folding, conformational stability, and functional activity of many peptides. A few disulfide-rich peptides with privileged architecture such as the inhibitor cystine knot motif have garnered attention as templates in drug design. The single disulfide-directed β-hairpin (SDH), a novel fold identified more recently in contryphan-Vc1, has been shown to possess remarkable thermal, conformational, and chemical stability and can accept a short bioactive epitope without compromising the core structure of the peptide. In this study, we demonstrated that the single disulfide bond is critical in maintaining the native fold by replacing both cysteine residues with serine. We also designed an analogue with an additional, non-native disulfide bridge by replacing Gln1 and Tyr9 with Cys. Contryphan-Vc11–22[Q1C, Y9C] was synthesised utilising orthogonal cysteine protection and its solution structure determined using solution NMR spectroscopy. This analogue maintained the overall fold of native contryphan-Vc1. Previous studies had shown that the β-hairpin core of contryphan-Vc1 was resistant to proteolysis by trypsin and α-chymotrypsin but susceptible to cleavage by pepsin. Contryphan-Vc11–22[Q1C, Y9C] proved to be completely resistant to pepsin, thus confirming our design strategy. These results highlight the role of the disulfide bond in maintaining the SDH fold and provide a basis for the design of more stable analogues for peptide epitope grafting.

FUNCTIONAL ROLE OF ACUTE PHASE PROTEINS IN CANCER CELLS

1996 ◽  
Vol 24 (4) ◽  
pp. 537S-537S
Author(s):  
Soo-Young Lee ◽  
Joo-Weon Lim ◽  
Jeong-Hee Kang
Keyword(s):  
Cancer Cells ◽  
Acute Phase ◽  
Functional Role ◽  
Acute Phase Proteins

scholarly journals Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Aamir Ahmad ◽  
Kevin R. Ginnebaugh ◽  
Shuping Yin ◽  
Aliccia Bollig-Fischer ◽  
Kaladhar B. Reddy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Functional Role ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Down Regulation ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Evolution Rescues Folding of Human Immunodeficiency Virus-1 Envelope Glycoprotein GP120 Lacking a Conserved Disulfide Bond

2008 ◽  
Vol 19 (11) ◽  
pp. 4707-4716 ◽  
Author(s):  
Rogier W. Sanders ◽  
Shang-Te D. Hsu ◽  
Eelco van Anken ◽  
I. Marije Liscaljet ◽  
Martijn Dankers ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Side Chain ◽  
Viral Glycoprotein ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Β Sheet

The majority of eukaryotic secretory and membrane proteins contain disulfide bonds, which are strongly conserved within protein families because of their crucial role in folding or function. The exact role of these disulfide bonds during folding is unclear. Using virus-driven evolution we generated a viral glycoprotein variant, which is functional despite the lack of an absolutely conserved disulfide bond that links two antiparallel β-strands in a six-stranded β-barrel. Molecular dynamics simulations revealed that improved hydrogen bonding and side chain packing led to stabilization of the β-barrel fold, implying that β-sheet preference codirects glycoprotein folding in vivo. Our results show that the interactions between two β-strands that are important for the formation and/or integrity of the β-barrel can be supported by either a disulfide bond or β-sheet favoring residues.

scholarly journals Role of Disulfide Bonds in Membrane Partitioning of a Viral Peptide

2021 ◽  
Author(s):  
Samapan Sikdar ◽  
Manidipa Banerjee ◽  
Satyavani Vemparala
Keyword(s):  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Hepatitis A Virus ◽  
Host Cells ◽  
Viral Peptide ◽  
Drug Designing ◽  
Helical Hairpin ◽  
2B Protein ◽  
Compact Conformation

AbstractThe importance of disulfide bond in mediating viral peptide entry into host cells is well known. In the present work, we elucidate the role of disulfide (SS) bond in partitioning mechanism of membrane active Hepatitis A Virus-2B (HAV-2B) peptide, which harbours three cysteine residues promoting formation of multiple SS-bonded states. The inclusion of SS-bond not only results in a compact conformation but also induces distorted α-helical hairpin geometry in comparison to SS-free state, resulting in reduced hydrophobic exposure. Owing to this, the partitioning of HAV-2B peptide is completely or partly abolished. In a way, the disulfide bond regulates the partitioning of HAV-2B peptide, such that the membrane remodelling effects of this viral peptide are significantly reduced. The current findings may have potential implications in drug designing, targeting the HAV-2B protein by promoting disulfide bond formation within its membrane active region.

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