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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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Alignment of LGI family members and domain organization.Multiple alignment of representative homologs in the LGI family. Species are abbreviated as follows: Hs = Homo sapiens; Mm = Mus musculus; Rn = Rattus norvegicus; Dr = Danio rerio; Xt = Xenopus tropicalis; Cf = Canis familiaris. The LGI1 domains and secondary structure are shown on the top part. Missense mutations analyzed in this paper (triangles) and putative glycosylation sites (stars) are indicated on the bottom of the alignment. Red lines are used to connect cysteine residues that form disulphide bridges in the structural model. acc: accessibility level from DSSP (black = high and white = low).
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pone-0018142-g002: Alignment of LGI family members and domain organization.Multiple alignment of representative homologs in the LGI family. Species are abbreviated as follows: Hs = Homo sapiens; Mm = Mus musculus; Rn = Rattus norvegicus; Dr = Danio rerio; Xt = Xenopus tropicalis; Cf = Canis familiaris. The LGI1 domains and secondary structure are shown on the top part. Missense mutations analyzed in this paper (triangles) and putative glycosylation sites (stars) are indicated on the bottom of the alignment. Red lines are used to connect cysteine residues that form disulphide bridges in the structural model. acc: accessibility level from DSSP (black = high and white = low).

Mentions: We defined boundaries of each domain in the LGI1 sequence (Figure 2). The first 35 N-terminal residues contain the signal peptide responsible for its secretion. A cleavage site is also predicted by SignalP in this region. The N-terminal part of the protein from residues 41 to 243 has about 30% sequence identity with LRR domain family proteins, while the C-terminal region between residues 245–552 contains the EPTP repeats. The two domains are also present in all human LGI proteins (LGI1, LGI2, LGI3, LGI4) and conserved across orthologs (Figure 2). Since a structure of LGI1 is not available, a structural analysis was conducted separately for the two domains as they have different characteristics.


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)

Alignment of LGI family members and domain organization.Multiple alignment of representative homologs in the LGI family. Species are abbreviated as follows: Hs = Homo sapiens; Mm = Mus musculus; Rn = Rattus norvegicus; Dr = Danio rerio; Xt = Xenopus tropicalis; Cf = Canis familiaris. The LGI1 domains and secondary structure are shown on the top part. Missense mutations analyzed in this paper (triangles) and putative glycosylation sites (stars) are indicated on the bottom of the alignment. Red lines are used to connect cysteine residues that form disulphide bridges in the structural model. acc: accessibility level from DSSP (black = high and white = low).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0018142-g002: Alignment of LGI family members and domain organization.Multiple alignment of representative homologs in the LGI family. Species are abbreviated as follows: Hs = Homo sapiens; Mm = Mus musculus; Rn = Rattus norvegicus; Dr = Danio rerio; Xt = Xenopus tropicalis; Cf = Canis familiaris. The LGI1 domains and secondary structure are shown on the top part. Missense mutations analyzed in this paper (triangles) and putative glycosylation sites (stars) are indicated on the bottom of the alignment. Red lines are used to connect cysteine residues that form disulphide bridges in the structural model. acc: accessibility level from DSSP (black = high and white = low).
Mentions: We defined boundaries of each domain in the LGI1 sequence (Figure 2). The first 35 N-terminal residues contain the signal peptide responsible for its secretion. A cleavage site is also predicted by SignalP in this region. The N-terminal part of the protein from residues 41 to 243 has about 30% sequence identity with LRR domain family proteins, while the C-terminal region between residues 245–552 contains the EPTP repeats. The two domains are also present in all human LGI proteins (LGI1, LGI2, LGI3, LGI4) and conserved across orthologs (Figure 2). Since a structure of LGI1 is not available, a structural analysis was conducted separately for the two domains as they have different characteristics.

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