Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

Poulson, Benjamin Gabriel; Szczepski, Kacper; Lachowicz, Joanna Izabela; Jaremko, Łukasz; Emwas, Abdul Hamid

doi:10.1039/c9ra09350h

Cited by 64 publications

(61 citation statements)

References 143 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on previous reports we expected some of these mice to show deposits [ 3 ] and we suggest that the lack thereof is due to the reduction of TGFBI R124H in heterozygotes and homozygotes as protein aggregations normally is concentration dependent. [ 13 ] Quantitation of mutated TGFBIp was not addressed in the original paper characterizing the TGFBI R124H mice that developed deposits. [ 3 ] Furthermore, the knock‐in construct does not contain introns, which can be a source of reduced transgene expression.…”

Section: Wt Heterozygote Homozygote No Accession Protein Name Molar mentioning

confidence: 99%

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

Lukassen

Poulsen

Donaghy

et al. 2020

Proteomics Clinical Apps

View full text Add to dashboard Cite

Purpose: Mutations in the transforming growth factor-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits. Experimental Design: The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS. Results: The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein. Conclusions and Clinical Relevance: It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.

show abstract

Section: Wt Heterozygote Homozygote No Accession Protein Name Molar mentioning

confidence: 99%

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

Lukassen

Poulsen

Donaghy

et al. 2020

Proteomics Clinical Apps

View full text Add to dashboard Cite

show abstract

“…Metals ions such as zinc where found to affect the process of protein aggregation which resulted in arise of amyloid like structures. Therefore, understanding the processes of aggregation and the factors related to them is crucial for creation of new drugs for amyloid related diseases [ 364 ]. In the experiment Lee et al used Ac-IHVHLQI-CONH 2 peptide (referred as HHQ) to form fibrils with varying Zn 2+ :HHQ molar ratios.…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

NMR as a “Gold Standard” Method in Drug Design and Discovery

et al. 2020

Self Cite

View full text Add to dashboard Cite

Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still a major challenge because pathogens rapidly and continually evolve developing drug resistance. Cancer cells also change genetically, and current therapeutic techniques may be (or may become) ineffective in many cases. The pathology of many neurological diseases remains an enigma, and the exact etiology and underlying mechanisms are still largely unknown. Viral infections spread and develop much more quickly than does the corresponding research needed to prevent and combat these infections; the present and most relevant outbreak of SARS-CoV-2, which originated in Wuhan, China, illustrates the critical and immediate need to improve drug design and development techniques. Modern day drug discovery is a time-consuming, expensive process. Each new drug takes in excess of 10 years to develop and costs on average more than a billion US dollars. This demonstrates the need of a complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played a critical role in drug discovery ever since its introduction several decades ago. In just three decades, NMR has become a “gold standard” platform technology in medical and pharmacology studies. In this review, we present the major applications of NMR spectroscopy in medical drug discovery and development. The basic concepts, theories, and applications of the most commonly used NMR techniques are presented. We also summarize the advantages and limitations of the primary NMR methods in drug development.

show abstract

“…The relatively small size of endo-lysosomal organelle when compared to the cytosol should also be considered a critical contributor of neurotoxic protein aggregation. Seeding aggregation of proteins is remarkably dependent on protein concentration and on the interaction with membranes ( Eisele et al, 2015 ; Poulson et al, 2020 ), whereby a threshold concentration has to be reached in order to initiate a nucleation-dependent polymerization ( Harper and Lansbury, 1997 ). Autosomal dominant disease forms bring clinical evidence of the correlation between protein concentration and pathogenicity.…”

Section: Autophagy–lysosome Dysfunction In Neurodegenerative Diseasesmentioning

confidence: 99%

Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside

Pedrioli

Paganetti

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Extracellular vesicles, phospholipid bilayer-membrane vesicles of cellular origin, are emerging as nanocarriers of biological information between cells. Extracellular vesicles transport virtually all biologically active macromolecules (e.g., nucleotides, lipids, and proteins), thus eliciting phenotypic changes in recipient cells. However, we only partially understand the cellular mechanisms driving the encounter of a soluble ligand transported in the lumen of extracellular vesicles with its cytosolic receptor: a step required to evoke a biologically relevant response. In this context, we review herein current evidence supporting the role of two well-described cellular transport pathways: the endocytic pathway as the main entry route for extracellular vesicles and the autophagic pathway driving lysosomal degradation of cytosolic proteins. The interplay between these pathways may result in the target engagement between an extracellular vesicle cargo protein and its cytosolic target within the acidic compartments of the cell. This mechanism of cell-to-cell communication may well own possible implications in the pathogenesis of neurodegenerative disorders.

show abstract

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

Abstract: The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not always a straightforward relationship.

Cited by 64 publications

References 143 publications

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

NMR as a “Gold Standard” Method in Drug Design and Discovery

Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside

Contact Info

Product

Resources

About

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

Abstract: The process of aggregation of proteins and peptides is dependent on the concentration of proteins, and the rate of aggregation can be altered by the presence of metal ions, but this dependence is not always a straightforward relationship.

Cited by 64 publications

References 143 publications

Protein Analysis of the TGFBIR124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

Protein Analysis of the TGFBIR124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

NMR as a “Gold Standard” Method in Drug Design and Discovery

Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside

Contact Info

Product

Resources

About

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy

Protein Analysis of the TGFBI^R124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy