In silico assessment of S100A12 monomer and dimer structural dynamics: implications for the understanding of its metal-induced conformational changes

Autor(es)

Garcia Reis, Renata Almeida ^[1] ; Bortot, Leandro Oliveira ^[2] ; Caliri, Antonio ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Cristalog Prot, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Lab Fis Biol, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY; v. 19, n. 7, p. 1113-1120, OCT 2014.
• Citações Web of Science: 1

Resumo

Changes in the concentration of different ions modulate several cellular processes, such as Ca2+ and Zn2+ in inflammation. Upon activation of immune system effector cells, the intracellular Ca2+ concentration rises propagating the activation signal, leading to degranulation and generation of reactive oxygen species, which increases the Zn2+ intracellular concentration as a consequence of the cellular antioxidant machinery. In this context, S100A12 is of special interest because it is a pro-inflammatory protein expressed in neutrophils whose structure and function are modulated by both Ca2+ and Zn2+. The current hypothesis about its mechanism of action was built based on biochemical and crystallographic data. However, there are missing connections between molecular structure and the way in which many events are concatenated at the triggering and along the inflammatory process. In this work we use molecular dynamics simulations to describe how variations in Zn2+ and Ca2+ concentrations modulate the structural dynamics of the calcium-free S100A12 dimer and monomer, which was not considered a part of the mechanism of action before. Our results suggest that (i) Zn2+ have a determinant role in the dimerization step, as well as in the unbinding of the Na+ complexed to the N-terminal EF-hand; (ii) the N-terminal EF-hand domain is the first to bind Ca2+, and not the C-terminal, as usually accepted; and that (iii) Ca2+ modulates the structural dynamics of H-III. (AU)

• Processo FAPESP: 10/01538-6 - Estudo dinâmico e conformacional da proteína calgranulina C (S100A12) mediante interação com íons bivalentes e receptor RAGE
• Beneficiário: Renata Almeida Garcia Reis
• Modalidade de apoio: Bolsas no Brasil - Mestrado