title: Computational analyses and prediction of guanylin deleterious SNPs.
abstract: Human guanylin, coded by the GUCA2A gene, is a member of a peptide family that activates intestinal membrane guanylate cyclase, regulating electrolyte and water transport in intestinal and renal epithelia. Deregulation of guanylin peptide activity has been associated with colon adenocarcinoma, adenoma and intestinal polyps. Besides, it is known that mutations on guanylin receptors could be involved in meconium ileus. However, there are no previous works regarding the alterations driven by single nucleotide polymorphisms in guanylin peptides. A comprehensive in silico analysis of missense SNPs present in the GUCA2A gene was performed taking into account 16 prediction tools in order to select the deleterious variations for further evaluation by molecular dynamics simulations (50 ns). Molecular dynamics data suggest that the three out of five variants (Cys104Arg, Cys112Ser and Cys115Tyr) have undergone structural modifications in terms of flexibility, volume and/or solvation. In addition, two nonsense SNPs were identified, both preventing the formation of disulfide bonds and resulting in the synthesis of truncated proteins. In summary the structural analysis of missense SNPs is important to decrease the number of potential mutations to be in vitro evaluated for associating them with some genetic diseases. In addition, data reported here could lead to a better understanding of structural and functional aspects of guanylin peptides.
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil.
authors.forename: William F
authors.initials: WF
authors.lastname: Porto
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; C S-Inova, Pos-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil. Electronic address: ocfranco@gmail.com.
authors.forename: Octávio L
authors.initials: OL
authors.lastname: Franco
authors.affiliation: Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil. Electronic address: sergiodealencar@gmail.com.
authors.forename: Sérgio A
authors.initials: SA
authors.lastname: Alencar
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D005768:Gastrointestinal Hormones / Q000737:chemistry / Q000235:genetics*; D030342:Genetic Diseases, Inborn; D006162:Guanylate Cyclase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D045265:Natriuretic Peptides / Q000737:chemistry / Q000235:genetics*; D010455:Peptides / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; C072685:guanylin; D006162:Guanylate Cyclase
keywords: Functional impact; GUCA2A; Guanylin; Missense SNPs; Molecular dynamics