title: Characterization of the neuron-specific L1-CAM cytoplasmic tail: naturally disordered in solution it exercises different binding modes for different adaptor proteins.
abstract: L1, a highly conserved transmembrane glycoprotein member of the immunoglobulin superfamily of cell adhesion molecules, mediates many developmental processes in the nervous system. Here we present the biophysical characterization and the binding properties of the least structurally defined part of this receptor: its cytoplasmic tail (CT). We have shown by analytical ultracentrifugation and dynamic light scattering experiments that it is mostly monomeric and unstructured in aqueous solution. We have defined by nuclear magnetic resonance the molecular details of L1-CT binding to two major targets: a membrane-cytoskeletal linker (MCL), ezrin, and an endocytosis mediator, AP2. Surprisingly, in addition to the two previously identified ezrin binding motifs, the juxtamembrane and the (1176)YRSLE regions, we have discovered a third one, a part of which has been previously associated with binding to another MCL, ankyrin. For the L1 interaction with AP2 we have determined the precise interaction region surrounding the (1176)YRSLE binding site and that this overlaps with the second ezrin binding site. In addition, we have shown that the juxtamembrane region of L1-CT has some binding affinity to AP2-mu2, although the specificity of this interaction needs further investigation. These data indicate that L1-CT belongs to the class of intrinsically disordered proteins. Endogenous flexibility of L1-CT might play an important role in dynamic regulation of intracellular signaling: the ability of cytoplasmic tails to accommodate different targets has the potential to fine-tune signal transduction via cell surface receptors.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Tyukhtenko
authors.forename: Lalit
authors.initials: L
authors.lastname: Deshmukh
authors.forename: Vineet
authors.initials: V
authors.lastname: Kumar
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lary
authors.forename: James
authors.initials: J
authors.lastname: Cole
authors.forename: Vance
authors.initials: V
authors.lastname: Lemmon
authors.forename: Olga
authors.initials: O
authors.lastname: Vinogradova
mesh_terms: D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D012996:Solutions; D014461:Ultracentrifugation
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D012996:Solutions