Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders.

Abstract

The L1 cell adhesion molecule has six domains homologous to members of the immunoglobulin superfamily and five homologous to fibronectin type III domains. We determined the outline structure of the L1 domains by showing that they have, at the key sites that determine conformation, residues similar to those in proteins of known structure. The outline structure describes the relative positions of residues, the major secondary structures and residue solvent accessibility. We use the outline structure to investigate the likely effects of 22 mutations that cause neurological diseases. The mutations are not randomly distributed but cluster in a few regions of the structure. They can be divided into those that act mainly by changing conformation or denaturing their domain and those that alter its surface properties.

An alcohol binding site on the neural cell adhesion molecule L1

“…Our model, based on the crystal structure of axonin (27), predicted a horseshoe structure similar to previous models based on the crystal structures of telokin and hemolin (19,29). The predicted distance of 2.8 Å between the photolabeled residues Glu-33 and Tyr-418 suggests that these two residues form a strong hydrogen bond that stabilizes the domain interaction between Ig1 and Ig4 and the horseshoe structure.…”

Neural Cell Adhesion Molecule (N-CAM) Homophilic Binding Mediated by the Two N-terminal Ig Domains Is Influenced by Intramolecular Domain-Domain Interactions

“…Thus, mutations that disrupt the presentation of binding sites on the cell surface are able to affect binding strength. An homology-based prediction of the structure of the adhesion molecule L1 has neighboring domains in contact (except for Ig2 and Ig3) and mapped many of the disease-associated mutations to the domain-domain interfaces (38). A similar homology based prediction on N-CAM suggests that its extracellular domains are also in contact, with short, 1-2 residue linker sequences between domains.…”

Organization of the Neurofascin Gene and Analysis of Developmentally Regulated Alternative Splicing

“…Here, we refine these positions on the basis of exon boundaries (Table I), which might define the domain boundaries more accurately and which is also supported by a key residue analysis of L1 (37). Most important, at the junction between the fourth FNIII-like repeat and the PAT domain, there is a sequence of five amino acid residues (ATPTP) that was originally assigned to the fourth FNIII-like repeat as it was not found to be alternatively spliced in conjunction with the PAT domain (17).…”

“…This interpretation is in line with studies on the structure of the related human L1. Key residue analysis of L1 indicates that Ig-like domains two and three are linked by amino acid residues that are not involved in ␤-sheet formation of the preceding or following Ig-like domain (37). In contrast, between Ig-like domains 1-2 and 3-6, such linking residues are absent and the last amino acid residue of the preceding and the first amino acid residue of the following Ig-like domain are parts of the ␤-sheet structures of the respective domains.…”