Abstract
The L1 family neural cell adhesion molecules play key roles in specifying the formation and remodeling of the neural network, but their homophilic interaction that mediates adhesion is not well understood. We report two crystal structures of a dimeric form of the headpiece of neurofascin, an L1 family member. The four N-terminal Ig-like domains of neurofascin form a horseshoe shape, akin to several other immunoglobulin superfamily cell adhesion molecules such as hemolin, axonin, and Dscam. The neurofascin dimer, captured in two crystal forms with independent packing patterns, reveals a pair of horseshoes in trans-synaptic adhesion mode. The adhesion interaction is mediated mostly by the second Ig-like domain, which features an intermolecular β-sheet formed by the joining of two individual GFC β-sheets and a large but loosely packed hydrophobic cluster. Mutagenesis combined with gel filtration assays suggested that the side chain hydrogen bonds at the intermolecular β-sheet are essential for the homophilic interaction and that the residues at the hydrophobic cluster play supplementary roles. Our structures reveal a conserved homophilic adhesion mode for the L1 family and also shed light on how the pathological mutations of L1 affect its structure and function.
Highlights
The atomic coordinates and structure factors have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ
These observations support the notion that neurofascin and L1 have a common adhesion mode, at least in the case when pairs are formed between two molecules from opposing membranes
We have reported the structures of a dimeric adhesion complex of the neurofascin N-terminal Ig domains in two independent crystal forms, which establish a general homophilic adhesion paradigm for the L1 family of neural cell adhesion molecules
Summary
The atomic coordinates and structure factors (codes 3P3Y and 3P40) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/). The four N-terminal Ig domains of these proteins are predicted to resemble a horseshoe, in which the first Ig domain (Ig1) L1 folds back to contact the fourth Ig domain (Ig4) (see Fig. 1A), similar to the crystal structures of the corresponding domains of several related Ig-CAMs, including hemolin [6], axonin-1 [7], and Dscam [8, 9]. The related Ig-CAM structures, including hemolin [6], axonin-1 [7, 19], and Dscam [8, 9], each indicated a different mode of horseshoe pairing; some suggested domain-swapping and zipper-like superassemblies. The recent cryo-electron tomography study of L1 suggests that the L1 adhesion does not fit the domain-swapping or zipper-like model but rather supports simple pairs of horseshoe heads, potentially cross-linked and regulated by carbohydrates [11]. The structures unambiguously reveal a mechanism illuminating how neurofascin achieves homophilic adhesion, which should be generally applicable for the L1 family CAMs
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