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

Leonardi E, Andreazza S, Vanin S, Busolin G, Nobile C, Tosatto SC - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padova, Padova, Italy.

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.

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Evolutionary relationship among the LGI vertebrate amino acid sequences.The figure shows the best likelihood tree (−lnL = −21148.01332) obtained using the PHYML program. The length of the branches represents the number of reconstructed change of state over all sites (bar represents 0.2 substitutions per site), bootstrap values are reported at the nodes. Blue squares indicate the fish sequences whereas the green and red arrows respectively the amphibian and bird sequences. An asterisk indicates the Ornithorhynchus anatinus protein.
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pone-0018142-g001: Evolutionary relationship among the LGI vertebrate amino acid sequences.The figure shows the best likelihood tree (−lnL = −21148.01332) obtained using the PHYML program. The length of the branches represents the number of reconstructed change of state over all sites (bar represents 0.2 substitutions per site), bootstrap values are reported at the nodes. Blue squares indicate the fish sequences whereas the green and red arrows respectively the amphibian and bird sequences. An asterisk indicates the Ornithorhynchus anatinus protein.

Mentions: The phylogenetic reconstruction was performed using 105 Vertebrate (Chordata; Chraniata) sequences. An additional sequence of Branchiostoma floridae (Chordata; Cephalochordata) has been included in the analysis. The obtained reconstruction reported in Figure 1 highlights the presence of 4 groups, named 1, 2, 3 and 4. The distribution pattern of LGI family transcripts in the adult mouse brain [49] highlights the tissue specificity of group 1 (see Figure 1).


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

Leonardi E, Andreazza S, Vanin S, Busolin G, Nobile C, Tosatto SC - PLoS ONE (2011)

Evolutionary relationship among the LGI vertebrate amino acid sequences.The figure shows the best likelihood tree (−lnL = −21148.01332) obtained using the PHYML program. The length of the branches represents the number of reconstructed change of state over all sites (bar represents 0.2 substitutions per site), bootstrap values are reported at the nodes. Blue squares indicate the fish sequences whereas the green and red arrows respectively the amphibian and bird sequences. An asterisk indicates the Ornithorhynchus anatinus protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3066209&req=5

pone-0018142-g001: Evolutionary relationship among the LGI vertebrate amino acid sequences.The figure shows the best likelihood tree (−lnL = −21148.01332) obtained using the PHYML program. The length of the branches represents the number of reconstructed change of state over all sites (bar represents 0.2 substitutions per site), bootstrap values are reported at the nodes. Blue squares indicate the fish sequences whereas the green and red arrows respectively the amphibian and bird sequences. An asterisk indicates the Ornithorhynchus anatinus protein.
Mentions: The phylogenetic reconstruction was performed using 105 Vertebrate (Chordata; Chraniata) sequences. An additional sequence of Branchiostoma floridae (Chordata; Cephalochordata) has been included in the analysis. The obtained reconstruction reported in Figure 1 highlights the presence of 4 groups, named 1, 2, 3 and 4. The distribution pattern of LGI family transcripts in the adult mouse brain [49] highlights the tissue specificity of group 1 (see Figure 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padova, Padova, Italy.

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.

Show MeSH
Related in: MedlinePlus