Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif

Ben-Shushan, Shira; Hecel, Aleksandra; Rowińska‐Żyrek, Magdalena; Kozłowski, Henryk; Miller, Yifat

doi:10.1021/acs.inorgchem.9b03199

Cited by 6 publications

(30 citation statements)

References 21 publications

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“… 53 Recently, we have shown a conformational change in solution for some of the tachykinins applying experimental and computational tools. 54 Interestingly, because of the rapid conformational change, the experimental techniques cannot be capable of recognizing all of the conformations of a particular tachykinin. For instance, a circular dichroism (CD) measurement of NKA in a solution environment showed a random coil structure by CD.…”

Section: Neuropeptides: Characterization and Functionsmentioning

confidence: 99%

“… 55 However, several partially helical structures of NKA in solution were distinguished using molecular dynamics (MD) simulations. 54 The explanation of the disagreement is due to the rapid conformational change that is seen in the MD simulations, and the experimental techniques are limited to introduce this process. Finally, in the presence of the membrane model, such as dodecylphosphocholine (DPC) micelles, the tachykinins exhibit helical conformations due to the hydrophobic environment.…”

Section: Neuropeptides: Characterization and Functionsmentioning

confidence: 99%

“…The Zn 2+ binding site in NKA was also investigated by a combination of experimental and computational tools in our group. 54 NKA has several residues that are capable of binding Zn 2+ ions. The potentiometric titrations were applied to examine the specific Zn 2+ binding site in NKA.…”

Section: Identification and Basic Elements Of Neuropeptides To Bind Metal Ionsmentioning

confidence: 99%

“…Recently, applying computational tools, we investigated the interactions of Zn 2+ ion in SP peptide. 54 Contrary to the numerous tachykinins, SP does not consist of residues prone to bind metal ions, such as His, Asp, Glu, etc. However, the carboxyl group of the C-terminal of SP has been proposed to be a potential site to bind Zn 2+ ion.…”

Section: Identification and Basic Elements Of Neuropeptides To Bind Metal Ionsmentioning

confidence: 99%

“…Recently, a molecular modeling study demonstrated that three of the tachykinins indeed bind Cu 2+ and Zn 2+ ions. 54 It is a hope that these studies will initiate future studies to investigate further neuropeptides that can bind metal ions. Importantly, the achievements from these studies may encourage investigations of these neuropeptides as metal chelators in vivo and later in clinical studies with AD and PD patients.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

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Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Ben-Shushan

Miller

2021

J. Phys. Chem. B

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Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by deposits of amyloid proteins. The homeostasis of metal ions is crucial for the normal biological functions in the brain. However, in AD and PD, the imbalance of metal ions leads to formation of amyloid deposits. In the past four decades, there has been extensive effort to design compound agents than can chelate metal ions with the aim of preventing the formation of the amyloid deposits. Unfortunately, the compounds to date that were designed were not successful candidates to be used in clinical trials. Neuropeptides are small molecules that are produced and released by neurons. It has been shown that neuropeptides have neuroprotective effects in the brain and reduce the formation of amyloid deposits. This Review Article is focused on the function of neuropeptides as metal chelators. Experimental and computational studies demonstrated that neuropeptides could bind metal ions, such as Cu 2+ and Zn 2+ . This Review Article provides perspectives and initiates future studies to investigate the role of neuropeptides as metal chelators in neurodegenerative diseases.

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Section: Neuropeptides: Characterization and Functionsmentioning

confidence: 99%

Section: Neuropeptides: Characterization and Functionsmentioning

confidence: 99%

Section: Identification and Basic Elements Of Neuropeptides To Bind Metal Ionsmentioning

confidence: 99%

Section: Identification and Basic Elements Of Neuropeptides To Bind Metal Ionsmentioning

confidence: 99%

Section: Summary and Future Perspectivesmentioning

confidence: 99%

See 3 more Smart Citations

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Ben-Shushan

Miller

2021

J. Phys. Chem. B

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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

et al. 2021

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The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin and zinc on the mechanism of aggregation of hIAPP. weight reduction was observed. In a phase-1 clinical trial in which AM833 was combined with the GLP-1-agonist Semaglutid, 20 weeks of treatment, participants lost an average of 17.1 % body weight. Overweight and obesity are risk factors for T2D and cardiovascular disease and the presented weight loss exceed reductions observed for GLP-1 and metformin. It should be noted that an IAPP derivative, pramlintide (symlin) is used, in addition to insulin, in patients with insulindependent T1D and T2D that have been difficult to regulate with insulin by a single drug. 42 Cross-correlation with other diseasesEpidemiological studies link diabetes with neurodegenerative diseases, including Alzheimer's disease [43][44][45][46] and Parkinson's disease. [47][48][49] The link is unclear, but the three conditions are multifactorial and have protein aggregation in their pathophysiology in common. If protein aggregation constitutes the link between these diseases, however, still needs to be proven. The Rotterdam study 50 , published in 1999, showed that patients with T2D have an almost doubled risk of developing dementia and Alzheimer's disease (AD). Data from the ULSAM study (Uppsala Longitudinal study of adult men) showed that already a moderate disturbance in the first-phase insulin release at the age of 55 increased the risk of developing AD thirty years later. 51 This suggests that diabetes precedes AD. In fact, another type of diabetes has been proposed [52][53][54] , which is type 3 diabetes (T3DM) which is an AD associated insulin resistance, also described as "brain diabetes phenotype". A considerable number of biophysical studies have shown a close link between the amyloid-forming proteins IAPP and Aβ. [55][56][57][58] IAPP immunoreactivity is present in formic acid brain extracts from patients with AD 59 and exhibited pattern on the western blot ranges from dimers to 16 mers. 60 The laddering pattern suggests that IAPP is present in the Aβ amyloid deposit. Proximity ligation assay (PLA) using two primary antibodies can be applied to determine the co-deposition of proteins. The positive PLA signal obtained after the combination of anti-IAPP and anti-Aβ antibodies points to the co-deposition of IAPP and Aβ in vivo. To confirm that the peptides interact in vivo, hIAPP transgenic mice were injected with preformed fibrils of Aβ followed by high-fat feeding for ten months. 60 Mice injected with preformed Aβ fibrils developed amyloid in 15% of the islets, which is comparable to mice injected with preformed fibrils of proIAPP. In mice injected with preformed IAPP fibrils, IAPP amyloid was found in 24 % of the islets. Control mice injected with fib...

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Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn²⁺ and Cu²⁺ Chelator

Ben-Shushan

Miller

2020

Inorg. Chem.

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The concept of metal chelation is based on simple coordination chemistry. The development of an ideal metal chelator that completely and selectively removes toxic metals from a specific metal binding site in proteins is required to prevent and or inhibit a variety of diseases, among them neurodegenerative diseases. This work examines neuropeptide Y (NPY) as a Zn 2+ and Cu 2+ chelator agent. NPY is a natural peptide that is produced in the human body; therefore, it is not a toxic agent and the complex that it forms is not toxic as well. Our simulations reveal that NPY has an efficient Zn 2+ chelation activity but is less effective in chelating Cu 2+ . Moreover, while NPY demonstrates several conformations, the metal chelation occurs more efficiently in its native structure. Beyond the exploration of the activity of NPY as a Zn 2+ and Cu 2+ chelator agent, this work provides an insight into the molecular mechanisms of the chelation of these metals at the molecular level. The outcomes from this work may guide future experimental studies to examine NPY in metal chelation therapy for neurodegenerative diseases.

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Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif

Cited by 6 publications

References 21 publications

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn²⁺ and Cu²⁺ Chelator

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Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif

Cited by 6 publications

References 21 publications

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Neuropeptides: Roles and Activities as Metal Chelators in Neurodegenerative Diseases

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn2+ and Cu2+ Chelator

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Molecular Mechanisms and Aspects on the Role of Neuropeptide Y as a Zn²⁺ and Cu²⁺ Chelator