Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities

Abstract

Mutations in the gene for neural cell adhesion molecule L1 (L1CAM) result in a debilitating X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecules including itself and two other CAMs of the immunoglobulin superfamily, axonin-1 and F11. However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of patient mutations are single amino acid changes distributed across 10 extracellular L1 domains. We have studied the effects of 12 missense mutations on binding to L1, axonin-1 and F11 and shown for the first time that whereas many mutations affect all three interactions, others affect homophilic or heterophilic binding alone. Patient pathology is therefore due to different types of L1 malfunction. The nature and functional consequence of mutation is also reflected in the severity of the resultant phenotype with structural mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular domains of L1 are required for homophilic and heterophilic interactions.

Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development

“…7 In cell-cell adhesion assay, Ninj1-transfected macrophages adhered to human umbilical vein endothelial cells 2.2 times more than mock (Mo)-transfected macrophages, which was reversed by Ninj1 antibody treatment (Figure 5c). Many adhesion molecules interact heterophilically as well as homophilically with their family members [28][29][30] and the possibility of heterophilic adhesion of Ninj1 has been also suggested. 19 They showed that peptides containing the adhesion motif of Ninj1 block the basal adhesion of wild-type Jurkat cells, indicating that other molecules with the Ninjurin-like adhesion motif may be involved in heterophilic interaction.…”

Signaling Lymphocytic Activation Molecule (CDw150) Is Homophilic but Self-associates with Very Low Affinity

“…The geometry of homophilic protein interactions at the cell surface varies between parallel "side-toside" interactions such as those observed for B7-1 (45), antiparallel side-to-side interactions as observed in the hemolin structure (46) and proposed for NCAM (47), L1 (48), and PECAM (49,50),…”

An alcohol binding site on the neural cell adhesion molecule L1

“…Indeed, binding of neurocan to L1 may inhibit L1 homophilic adhesion by stabilizing the linear conformation of Ig1-4 (18). The potential importance of the horseshoe structure of L1 is underscored by the conservation of residues across species at the domain interfaces between Ig1 to Ig4 and Ig2 to Ig3 and the disproportionate number of these residues in which missense mutations cause developmental abnormalities of the nervous system (21,22,29).…”

“…The Leu-120-Val mutation results in the loss of Sema3A regulation of L1-neuropilin interactions but does not affect L1 homophilic binding (30). On the other hand, the Gly-121-Ser mutation reduces L1 homophilic binding by 90% and decreases L1 interactions with F11 and contactin (21). Thus, the binding of ethanol in the region of these disease-causing mutations could disrupt development by inhibiting homophilic or heterophilic interactions of L1.…”

“…A long linker region between Ig2 and Ig3 enables the Ig1 and Ig2 domains to fold over and contact the Ig3 and Ig4 domains, forming a horseshoe structure that may facilitate L1-L1 interactions (18)(19)(20). The importance of this quaternary structure on L1 function is suggested by the disproportionate number of disease-causing missense mutations located at Ig domain interfaces, many of which reduce L1 homophilic binding (21,22).…”