Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination.
The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.
Erasmus University Medical Center, Biomedical Sciences, Departments of Genetics and Cell Biology, Rotterdam 3015GE, The Netherlands.
Linde
L
Kegel
Martine
M
Jaegle
Siska
S
Driegen
Eerik
E
Aunin
Kris
K
Leslie
Yuko
Y
Fukata
Masahiko
M
Watanabe
Masaki
M
Fukata
Dies
D
Meijer
D051722:ADAM Proteins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D017124:Conserved Sequence; D005816:Genetic Complementation Test; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009928:Organ Specificity; D017933:Peripheral Nervous System / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D015027:Zebrafish
D000596:Amino Acids; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D051722:ADAM Proteins; C121259:Adam23 protein, mouse
ADAM23; Evolution and development; Leucine-rich glioma-inactivated; Mouse; Myelination; Schwann cell