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Structure of fibronectin 2 and 3 of L1CAM at 2.0 Angstrom
Structural highlights
DiseaseL1CAM_HUMAN Hydrocephalus with stenosis of the aqueduct of Sylvius;MASA syndrome;X-linked complicated spastic paraplegia type 1;X-linked complicated corpus callosum dysgenesis. The disease is caused by variants affecting the gene represented in this entry. L1CAM mutations have also been found in few patients affected by hydrocephalus with Hirschsprung disease, suggesting a role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease (PubMed:22344793).[1] The disease is caused by variants affecting the gene represented in this entry. Defects in L1CAM may contribute to Hirschsprung disease by modifying the effects of Hirschsprung disease-associated genes to cause intestinal aganglionosis.[2] The disease is caused by variants affecting the gene represented in this entry. Defects in L1CAM are associated with a wide phenotypic spectrum which varies from severe hydrocephalus and prenatal death (HYCX) to a milder phenotype (MASA). These variations may even occur within the same family. Due to the overlap of phenotypes between HYCX and MASA, many authors use the general concept of L1 syndrome which covers both ends of the spectrum.[3] [4] [5] FunctionL1CAM_HUMAN Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors. During brain development, critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis. In the mature brain, plays a role in the dynamics of neuronal structure and function, including synaptic plasticity.[6] Publication Abstract from PubMedThe cell adhesion molecule L1 (L1CAM, L1 in short) plays crucial roles during neural development, regeneration after injury, synapse formation, synaptic plasticity and tumor cell migration. L1 belongs to the immunoglobulin superfamily and comprises in its extracellular part six immunoglobulin (Ig)-like domains and five fibronectin type III homologous repeats (FNs). The second Ig-like domain has been validated for self- (so-called homophilic) binding between cells. Antibodies against this domain inhibit neuronal migration in vitro and in vivo. The fibronectin type III homologous repeats FN2 and FN3 bind small molecule agonistic L1 mimetics and contribute to signal transduction. FN3 has a stretch of 25 amino acids that can be triggered with a monoclonal antibody, or the L1 mimetics, to enhance neurite outgrowth and neuronal cell migration in vitro and in vivo. To correlate the structural features of these FNs with function, we determined a high-resolution crystal structure of a FN2FN3 fragment, which is functionally active in cerebellar granule cells and binds several mimetics. The structure illustrates that both domains are connected by a short linker sequence allowing a flexible and largely independent organization of both domains. This becomes further evident by comparing the X-ray crystal structure with models derived from Small-Angle X-ray Scattering (SAXS) data for FN2FN3 in solution. Based on the X-ray crystal structure, we identified five glycosylation sites which we believe are crucial for folding and stability of these domains. Our study signifies an advance in the understanding of structure-functional relationships of L1. X-ray structure and function of fibronectin domains two and three of the neural cell adhesion molecule L1.,Guedez G, Loers G, Jeffries CM, Kozak S, Meijers R, Svergun DI, Schachner M, Low C FASEB J. 2023 Mar;37(3):e22823. doi: 10.1096/fj.202201511R. PMID:36809668[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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