Disulfide bonds in amyloidogenesis diseases related proteins

Li, Yang; Yan, Juan; Zhang, Xin; Huang, Kun

doi:10.1002/prot.24338

Cited by 63 publications

(55 citation statements)

References 140 publications

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“…All sequenced CTs are 32 residues in length and have an intramolecular disulfide bridge (Cys1‐Cys7), but sequence homology varies significantly from species to species, with hCT differing from other CTs by as few as 2 residues (murine CT) or as many as 19 residues (ovine CT) ,. Interestingly, the presence of the N‐terminal disulfide bond is well conserved across all known calcitonin sequences, a feature commonly thought to reduce amyloidogenic aggregation . A comparative alignment of several commonly studied calcitonin peptide sequences is shown in Figure .…”

Section: Introductionmentioning

confidence: 99%

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

Kamgar-Parsi

Tolchard

Habenstein

et al. 2016

Israel Journal of Chemistry

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Under appropriate conditions, peptides and proteins can assemble from their native state into prefibrillar oligomers and then mature into fibrillar aggregates. This transition forms the molecular basis of several pathologies, often related to the deposition of these amyloid fibrils. Several hormone peptides involved in fundamental biological processes have the tendency to self‐assemble into amyloid fibrils, resulting in a loss of their native functions, and more importantly, entailing devastating consequences, such as the formation of amyloid depositions. Calcitonin is a 32 amino‐acid hormone peptide that can be considered a molecular paradigm for the central events associated with hormone misfolding. Calcitonin in its native form is involved in various physiological functions, including mediating calcium homeostasis and maintaining bone structure. It is the latter function that has motivated the use of calcitonin as an aqueous therapeutic agent for the treatment of bone‐related pathologies such as osteoporosis and Paget's disease. Despite some success as a therapeutic, calcitonin's ability to control these diseases is limited by its aggregation along the canonical amyloid aggregation pathway, compromising its long‐term stability as a therapeutic agent. A better understanding of the misfolding process would not only provide the structural basis to improve calcitonin's long‐term stability and activity as a therapeutic, but also provide valuable insights into pathological aggregation of other amyloids. In this work, we review the physiological roles of calcitonin, its structure, and aggregation process, and consider the effects of calcitonin's structure on its role as a therapeutic.

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Section: Introductionmentioning

confidence: 99%

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

Kamgar-Parsi

Tolchard

Habenstein

et al. 2016

Israel Journal of Chemistry

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“…One of the essential factors governing protein/peptide structure and stability is the disulfide bond (10 -12). The role of disulfide bond on structure, oligomerization, and amyloidogenicity of several proteins relevant to diseases/biological functions has previously been postulated by various research groups (10,(13)(14)(15).…”

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confidence: 99%

Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

Arunagiri

Ranganathan

Dhaked

et al. 2014

Journal of Biological Chemistry

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Background: Peptide/protein hormones are stored as amyloids within endocrine secretory granules. Results: Disulfide bond cleavage enhances conformational dynamics and aggregation kinetics in somatostatin-14, resulting in amyloid fibrils with increased resistance to denaturing conditions and decreased reversibility. Conclusion: Disulfide bond could be a key modulating factor in somatostatin-14 amyloid formation associated with secretory granule biogenesis. Significance: Defective disulfide bonding might cause dysregulation of hormone storage/secretion.

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“…Despite these notable sources of noise (40,49), we detected several statistically significant substitutions that are enriched or depleted within specific PTMs. Particularly salient are functional contexts with clinical implications such as cysteine disulfide bonds (50), phosphotyrosine (relative to phosphoserine and phosphothreonine) (51) and ion-binding sites (52). Many rare monogenic diseases result from point mutations in codons of cysteine, which destroy essential disulfide bridges bonds (50).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary and Functional Lessons from Human-Specific Amino-Acid Substitution Matrices

Shauli

Brandes

Linial

2020

Preprint

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The characterization of human genetic variation in coding regions is fundamental to our understanding of protein function, structure, and evolution. Amino-acid (AA) substitution matrices such as BLOSUM (BLOcks SUbstitution Matrix) and PAM (Point Accepted Mutations) encapsulate the stochastic nature of such proteomic variation and are used in studying protein families and evolutionary processes. However, these matrices were constructed from protein sequences spanning long evolutionary distances and are not designed to reflect polymorphism within species. To accurately represent proteomic variation within the human population, we constructed a set of human-centric substitution matrices derived from genetic variations by analyzing the frequencies of >4.8M single nucleotide variants (SNVs). These human-specific matrices expose short-term evolutionary trends at both codon and AA resolution and therefore present an evolutionary perspective that differs from that implicated in the traditional matrices. Specifically, our matrices consider the directionality of variants, and uncover a set of AA pairs that exhibit a strong tendency to substitute in a specific direction. We further demonstrate that the substitution rates of nucleotides only partially determine AA substitution rates. Finally, we investigate AA substitutions in posttranslational modification (PTM) and ion-binding sites. We confirm a strong propensity towards conservation of the identity of the AA that participates in such functions. The empirically-derived human-specific substitution matrices expose purifying selection over a range of residue-based protein properties. The new substitution matrices provide a robust baseline for the analysis of protein variations in health and disease. The underlying methodology is available as an openaccess to the biomedical community.

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Disulfide bonds in amyloidogenesis diseases related proteins

Cited by 63 publications

References 140 publications

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

Evolutionary and Functional Lessons from Human-Specific Amino-Acid Substitution Matrices

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