Study of molecular mechanisms of UV-induced aggregation of crystallins and possibility of maintaining eye lens transparency

2006 ◽  
Author(s):  
L. V. Soustov ◽  
E. V. Chelnokov ◽  
N. M. Bityurin ◽  
A. L. Kiselev ◽  
V. V. Nemov ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Eye Lens ◽  
Lens Transparency ◽  
Induced Aggregation

scholarly journals Metal ions and redox balance regulate distinct amyloid-like aggregation pathways of GAPR-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jie Sheng ◽  
Nick K. Olrichs ◽  
Willie J. Geerts ◽  
Dora V. Kaloyanova ◽  
J. Bernd Helms
Keyword(s):  
Metal Ions ◽  
Metal Binding ◽  
Molecular Mechanisms ◽  
Quaternary Structure ◽  
Copper Ions ◽  
Redox Homeostasis ◽  
Secretory Proteins ◽  
Pathogenesis Related Protein ◽  
Pathogenesis Related ◽  
Induced Aggregation

Abstract Members of the CAP superfamily (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-Related 1 proteins) are characterized by the presence of a structurally conserved CAP domain. The common structure-function relationship of this domain is still poorly understood. In this study, we unravel specific molecular mechanisms modulating the quaternary structure of the mammalian CAP protein GAPR-1 (Golgi-Associated plant Pathogenesis-Related protein 1). Copper ions are shown to induce a distinct amyloid-like aggregation pathway of GAPR-1 in the presence of heparin. This involves an immediate shift from native multimers to monomers which are prone to form amyloid-like fibrils. The Cu2+-induced aggregation pathway is independent of a conserved metal-binding site and involves the formation of disulfide bonds during the nucleation process. The elongation process occurs independently of the presence of Cu2+ ions, and amyloid-like aggregation can proceed under oxidative conditions. In contrast, the Zn2+-dependent aggregation pathway was found to be independent of cysteines and was reversible upon removal of Zn2+ ions. Together, our results provide insight into the regulation of the quaternary structure of GAPR-1 by metal ions and redox homeostasis with potential implications for regulatory mechanisms of other CAP proteins.

Antiplatelet Actions Of Low Molecular Weight Peptides And Their Derivatives

1981 ◽  
Author(s):  
Jawed Fareed ◽  
Harry L Messmore ◽  
Daniel A Walz
Keyword(s):  
Molecular Weight ◽  
Molecular Mechanisms ◽  
Free Acid ◽  
Acid Amide ◽  
Antiplatelet Agents ◽  
Low Molecular Weight ◽  
Clot Retraction ◽  
Induced Aggregation ◽  
Derivatives Of ◽  
Aggregation Of Platelets

We have reported on the antiserine protease actions of low molecular weight peptides with arginine and lysine at the carboxyl terminus and their derivatives. In order to investigate the action of these peptides and their analogues on other components of hemostasis we studied their effects on platelet function; aggregation and release reactions, clot retraction and serotonin uptake by platelets. D-Phe-Pro-Arg-NH-heptyl, D-Phe-Pro-Arg-O-heptyl, D-Phe-Pro-Arg-thiobenzyl, D-Phe-Pro-Arg-COOH, D-Phe-Pro-Arg-NH2, D-Phe-Pro-Arginal and similar derivatives of D-Pro-Phe-Arg, D-Phe-Phe-Arg and Val-leu-lys- were screened None of these peptides produced aggregation and release reactions in concentration >10 mM. D-Phe-Pro-Arg-thiobenzyl and D-Phe-Pro-Arginal produced a strong inhibition of thrombin induced aggregation and release reactions at sub ymolar levels. Both of these peptides also inhibited thrombin’s action in amidolytic and coagulant assays. D-Phe-Pro-Arg-thiobenzyl ester also produced a complete inhibition of arachidonic acid induced aggregation of platelets and showed varying inhibitory actions against ADP, epinephrine, collagen, and serotonin induced aggregation and release reactions. Although ristocetin induced aggregation was only slightly effected, a complete block of the release reaction was seen. ADP induced β-thrombo- globulin release was also inhibited by this peptide.Heptyl amide and esters of H-D-Phe-Pro-Arg-and free acid, amide and arginal forms of various other peptides exhibited relatively weaker antiplatelet actions. Our studies suggest that peptides with amino acid resembling serine protease sensitive sites can be molecularly manipulated to design potent antiplatelet agents. Furthermore these peptides may provide a useful probe to study the molecular mechanisms involved in the pathophysiology of thrombotic disorders and to design new antiplatelet drugs.

scholarly journals Eph-ephrin Signaling Affects Eye Lens Fiber Cell Intracellular Voltage and Membrane Conductance

2021 ◽  
Vol 12 ◽  
Author(s):  
Catherine Cheng ◽  
Junyuan Gao ◽  
Xiurong Sun ◽  
Richard T. Mathias
Keyword(s):  
Cell Membrane ◽  
Water Channel ◽  
Membrane Conductance ◽  
Building Blocks ◽  
Fiber Cell ◽  
Eye Lens ◽  
Lens Fiber ◽  
Fiber Cells ◽  
Lens Fibers ◽  
Lens Transparency

The avascular eye lens generates its own microcirculation that is required for maintaining lifelong lens transparency. The microcirculation relies on sodium ion flux, an extensive network of gap junction (GJ) plaques between lens fiber cells and transmembrane water channels. Disruption of connexin proteins, the building blocks of GJs, or aquaporins, which make up water and adhesion channels, lead to lens opacification or cataracts. Recent studies have revealed that disruption of Eph-ephrin signaling, in particular the receptor EphA2 and the ligand ephrin-A5, in humans and mice lead to congenital and age-related cataracts. We investigated whether changes in lens transparency in EphA2 or ephrin-A5 knockout (–/–) mice is related to changes in GJ coupling and lens fluid and ion homeostasis. Immunostaining revealed changes in connexin 50 (Cx50) subcellular localization in EphA2–/– peripheral lens fibers and alteration in aquaporin 0 (Aqp0) staining patterns in ephrin-A5–/– and EphA2–/– inner mature fiber cells. Surprisingly, there was no obvious change in GJ coupling in knockout lenses. However, there were changes in fiber cell membrane conductance and intracellular voltage in knockout lenses from 3-month-old mice. These knockout lenses displayed decreased conductance of mature fiber membranes and were hyperpolarized compared to control lenses. This is the first demonstration that the membrane conductance of lens fibers can be regulated. Together these data suggest that EphA2 may be needed for normal Cx50 localization to the cell membrane and that conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel localization.

scholarly journals Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

2017 ◽  
Vol 37 (17) ◽  
Author(s):  
Therese Jacobson ◽  
Smriti Priya ◽  
Sandeep K. Sharma ◽  
Stefanie Andersson ◽  
Sofia Jakobsson ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cadmium Toxicity ◽  
Cytosolic Proteins ◽  
Content Type ◽  
Folded Proteins ◽  
Protein Folding Disorders ◽  
Induced Aggregation

ABSTRACT Cadmium is a highly poisonous metal and is classified as a human carcinogen. While its toxicity is undisputed, the underlying in vivo molecular mechanisms are not fully understood. Here, we demonstrate that cadmium induces aggregation of cytosolic proteins in living Saccharomyces cerevisiae cells. Cadmium primarily targets proteins in the process of synthesis or folding, probably by interacting with exposed thiol groups in not-yet-folded proteins. On the basis of in vitro and in vivo data, we show that cadmium-aggregated proteins form seeds that increase the misfolding of other proteins. Cells that cannot efficiently protect the proteome from cadmium-induced aggregation or clear the cytosol of protein aggregates are sensitized to cadmium. Thus, protein aggregation may contribute to cadmium toxicity. This is the first report on how cadmium causes misfolding and aggregation of cytosolic proteins in vivo. The proposed mechanism might explain not only the molecular basis of the toxic effects of cadmium but also the suggested role of this poisonous metal in the pathogenesis of certain protein-folding disorders.

scholarly journals Structural Integrity of the Greek Key Motif in βγ-Crystallins Is Vital for Central Eye Lens Transparency

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70336 ◽  
Author(s):  
Venkata Pulla Rao Vendra ◽  
Garima Agarwal ◽  
Sushil Chandani ◽  
Venu Talla ◽  
Narayanaswamy Srinivasan ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Eye Lens ◽  
Lens Transparency

scholarly journals Melanosomes in pigmented epithelia maintain eye lens transparency during zebrafish embryonic development

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Masanari Takamiya ◽  
Feng Xu ◽  
Heikki Suhonen ◽  
Victor Gourain ◽  
Lixin Yang ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Eye Lens ◽  
Lens Transparency
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