Theoretical structural characterization of lymphoguanylin: A potential candidate for the development of drugs to treat gastrointestinal disorders

Pires, Állan S.; Porto, William F.; Castro, Pryscilla O.; Franco, Octávio L.; Alencar, Sérgio Amorim de

doi:10.1016/j.jtbi.2017.02.016

Cited by 9 publications

(7 citation statements)

References 49 publications

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“…In uroguanylin, two N-terminal aspartic acid residues were shown to act as an acidic switch, altering the protein conformation and enhancing ligand-receptor affinity 100-fold at pH 5 vs. pH 8 ( 40 , 41 ). However, recent molecular dynamics simulations of lymphoguanylin suggest that the hydrophobic core, rather than the acidic N-terminal residues, controls peptide conformation ( 42 ). Despite our evolving understanding of the molecular behavior of these peptides, it is clear that differences in pH sensitivity of the ligands parallel their expression profiles along the intestinal axis, with uroguanylin expressed in the acidic environment of the duodenum, and guanylin expressed in the neutral environment of the colorectum ( 22 ).…”

Section: Components Of the Intestinal Cgmp Signaling Axismentioning

confidence: 99%

“…Interestingly, lymphoguanylin and a recently-identified mutant form of human guanylin (C115Y) harbor a C-terminal tyrosine residue in place of the typical cysteine, eliminating one disulfide bridge in these species and lowering their potency to activate GUCY2C (Figure 3 ) ( 45 ). Recent single nucleotide polymorphism and structural analyses of guanylin peptide variants have lent insights into features that can be exploited to develop new compounds in this growing class of pharmaceutics ( 42 , 45 , 46 ).…”

Section: Components Of the Intestinal Cgmp Signaling Axismentioning

confidence: 99%

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The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

Rappaport

2018

Front. Oncol.

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Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses to DNA damage, epithelial-mesenchymal cross-talk, cell migration, and cellular metabolic status. Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer. This review explores the current understanding of cGMP signaling in the intestinal epithelium and mechanisms by which it opposes intestinal injury. Particular focus will be applied to its emerging role in tumor suppression. In colorectal tumors, endogenous GUCY2C ligand expression is lost by a yet undefined mechanism conserved in mice and humans. Further, reconstitution of GUCY2C signaling through genetic or oral ligand replacement opposes tumorigenesis in mice. Taken together, these findings suggest an intriguing hypothesis that colorectal cancer arises in a microenvironment of functional GUCY2C inactivation, which can be repaired by oral ligand replacement. Hence, the GUCY2C signaling axis represents a novel therapeutic target for preventing colorectal cancer.

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Section: Components Of the Intestinal Cgmp Signaling Axismentioning

confidence: 99%

Section: Components Of the Intestinal Cgmp Signaling Axismentioning

confidence: 99%

The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

Rappaport

2018

Front. Oncol.

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“…Then, to improve the accuracy of the predictions, other techniques, such as molecular dynamics, can be used [21]. This approach has been used by our group to study other mutations related to peptide hormones, such as guanylin [22], uroguanylin [23], lymphoguanylin [24] and growth hormone receptor [25]. Here we show that the rare mutations in mature amylin caused by SNPs are located in conserved position, maintaining the aggregation potential and a similar structure conformation to the wild-type after an unfolding dynamics simulation.…”

Section: Introductionmentioning

confidence: 99%

“…Then, to improve the accuracy of predictions, other techniques, such as molecular dynamics, can be used [21]–[25]. This approach has been used by our group to study other mutations related to peptide hormones, such as guanylin [26], uroguanylin [27], lymphoguanylin [28] and growth hormone receptor [29]. Our hypothesis is that mutations in the amylin gene can alter the peptide structure.…”

Section: Introductionmentioning

confidence: 99%

Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide

Mendes

Franco

Alencar

et al. 2021

Preprint

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Amylin is a 37 amino acid peptide hormone co-secreted with insulin, which participates in the glucose homeostasis. This hormone is able to aggregate in a β-sheet conformation and deposit in islet amyloids, a hallmark in type II diabetes. Since amylin is a gene encoded hormone, this peptide has variants caused by single nucleotide polymorphisms (SNPs) that can impact its functions. The effect of these variants can be evaluated by means of computational tools, such as molecular dynamics simulations. Here, we analyzed the structural effects caused by S20G and G33R point mutations, which, according to the 1,000 Genomes Project, have frequency in East Asian and Europe populations, respectively. By means of the aggrescan software and molecular dynamics, we found that both mutations have aggregation potential and cause changes in the monomeric forms when compared with wild-type amylin. The S20G mutation has been described as pathological related, and G33R mutation may have a deleterious effect. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed inferring the second α-helix maintenance may be related to the aggregation potential. Our data could help to better understand the mutations influence in the wild-type amylin sequence, being a starting point for the evaluation and characterization of other variations. The data presented here also propitiate new therapy opportunities, whether creating more effective drugs to diabetes or implementing a specific treatment to the patients with these mutations. Hence, these findings could improve the lifestyle to patients with type II diabetes.

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“…However, these tools have presented limitations in benchmarking analyses using specific proteins [16][17][18][19] and for this reason, further evaluation by molecular dynamics simulations is required. This approach has been applied by our group to study SNP effects in different peptides, including guanylins [20][21][22] and defensins [23,24]; and also larger proteins, including growth hormone receptor [25], apolipoprotein E [26] and glucocorticoid receptor [27]. In the present work, we applied a similar strategy to assess the effects of missense SNPs on LL-37 structure, showing the SNPs did not affect the residues from the active core of LL-37; however they could influence the antimicrobial activity by altering the positive net charge, helix dipole and/or the α -helix structure.…”

Section: Introductionmentioning

confidence: 99%

In silicoassessment of missense point mutations on human cathelicidin LL-37

Alencar

2021

Preprint

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Cathelicidin antimicrobial peptides are a diverse family of cationic amphipathic peptides with multiple activities. In humans, cathelicidin LL-37 is one of the main host defense peptides with a remarkable medical and biotechnological potential. Deregulation of LL-37 expression has been associated with inflammatory diseases. However the effects of point mutations driven by single nucleotide polymorphisms (SNPs) on LL-37 are unknown. Here we applied an array of computational tools to investigate the effects of such mutations on LL-37 structure and activity. Due to the fact that, on cathelicidins, the prodomain is more conserved than the mature peptide, the SNP effect predictions were biased and, overall, resulted in neutral effects; and due to the slight changes in physicochemical properties, the antimicrobial predictions indicated the maintenance of such activity. Nonetheless, six out of eleven mutations altered the positive net charge, which in turn could result in less active LL-37 variants. Molecular dynamics data indicated that R07Q and N30Y mutations altered the LL-37 structure. In addition to these ones, the G03A, R07P, R07W and L31P mutations altered the helix dipole, which could also alter the antimicrobial activity. Our results indicated despite the mutations did not alter the residues from LL-37 active core, they could influence the antimicrobial activity and consequently, could be involved in inflammatory diseases.

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Theoretical structural characterization of lymphoguanylin: A potential candidate for the development of drugs to treat gastrointestinal disorders

Cited by 9 publications

References 49 publications

The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide

In silicoassessment of missense point mutations on human cathelicidin LL-37

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