A computational model of the LGI1 protein suggests a common binding site for ADAM proteins

Emanuela Leonardi, Simonetta Andreazza, Stefano Vanin, Giorgia Busolin, Carlo Nobile, Silvio C E Tosatto

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Mutations of human leucine-rich glioma inactivated (LGI1) gene encoding the epitempin protein cause autosomal dominant temporal lateral epilepsy (ADTLE), a rare familial partial epileptic syndrome. The LGI1 gene seems to have a role on the transmission of neuronal messages but the exact molecular mechanism remains unclear. In contrast to other genes involved in epileptic disorders, epitempin shows no homology with known ion channel genes but contains two domains, composed of repeated structural units, known to mediate protein-protein interactions. A three dimensional in silico model of the two epitempin domains was built to predict the structure-function relationship and propose a functional model integrating previous experimental findings. Conserved and electrostatic charged regions of the model surface suggest a possible arrangement between the two domains and identifies a possible ADAM protein binding site in the β-propeller domain and another protein binding site in the leucine-rich repeat domain. The functional model indicates that epitempin could mediate the interaction between proteins localized to different synaptic sides in a static way, by forming a dimer, or in a dynamic way, by binding proteins at different times. The model was also used to predict effects of known disease-causing missense mutations. Most of the variants are predicted to alter protein folding while several other map to functional surface regions. In agreement with experimental evidence, this suggests that non-secreted LGI1 mutants could be retained within the cell by quality control mechanisms or by altering interactions required for the secretion process.

LanguageEnglish
Article numbere18142
Number of pages13
JournalPLoS One
Volume6
Issue number3
DOIs
Publication statusPublished - 29 Mar 2011

Fingerprint

ADAM Proteins
binding sites
Binding Sites
Protein Binding
Leucine
Genes
protein binding
Proteins
proteins
leucine
genes
Temporal Lobe Epilepsy
Secretory Pathway
Protein Folding
Missense Mutation
Protein folding
Static Electricity
Ion Channels
missense mutation
Gene encoding

Cite this

Leonardi, E., Andreazza, S., Vanin, S., Busolin, G., Nobile, C., & Tosatto, S. C. E. (2011). A computational model of the LGI1 protein suggests a common binding site for ADAM proteins. PLoS One, 6(3), [e18142]. https://doi.org/10.1371/journal.pone.0018142
Leonardi, Emanuela ; Andreazza, Simonetta ; Vanin, Stefano ; Busolin, Giorgia ; Nobile, Carlo ; Tosatto, Silvio C E. / A computational model of the LGI1 protein suggests a common binding site for ADAM proteins. In: PLoS One. 2011 ; Vol. 6, No. 3.
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Leonardi, E, Andreazza, S, Vanin, S, Busolin, G, Nobile, C & Tosatto, SCE 2011, 'A computational model of the LGI1 protein suggests a common binding site for ADAM proteins', PLoS One, vol. 6, no. 3, e18142. https://doi.org/10.1371/journal.pone.0018142

A computational model of the LGI1 protein suggests a common binding site for ADAM proteins. / Leonardi, Emanuela; Andreazza, Simonetta; Vanin, Stefano; Busolin, Giorgia; Nobile, Carlo; Tosatto, Silvio C E.

In: PLoS One, Vol. 6, No. 3, e18142, 29.03.2011.

Research output: Contribution to journalArticle

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Leonardi E, Andreazza S, Vanin S, Busolin G, Nobile C, Tosatto SCE. A computational model of the LGI1 protein suggests a common binding site for ADAM proteins. PLoS One. 2011 Mar 29;6(3). e18142. https://doi.org/10.1371/journal.pone.0018142