Contactin-associated protein-like 2 (CNTNAP2) encodes for CASPR2, a multidomain single transmembrane protein belonging to the neurexin superfamily that has been implicated in a broad range of human phenotypes including autism and language impairment. Using a combination of biophysical techniques, including small angle x-ray scattering, single particle electron microscopy, analytical ultracentrifugation, and bio-layer interferometry, we present novel structural and functional data that relate the architecture of the extracellular domain of CASPR2 to a previously unknown ligand, Contactin1 (CNTN1). Structurally, CASPR2 is highly glycosylated and has an overall compact architecture. Functionally, we show that CASPR2 associates with micromolar affinity with CNTN1 but, under the same conditions, it does not interact with any of the other members of the contactin family. Moreover, by using dissociated hippocampal neurons we show that microbeads loaded with CASPR2, but not with a deletion mutant, co-localize with transfected CNTN1, suggesting that CNTN1 is an endogenous ligand for CASPR2. These data provide novel insights into the structure and function of CASPR2, suggesting a complex role of CASPR2 in the nervous system.
Pubmed ID: 26721881 RIS Download
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Biomedical technology research center that develops computer-aided, advanced microscopy for the acquisition of structural and functional data in the dimensional range of 1 nm to 100 um, a range encompassing macromolecules, subcellular structures and cells. Novel specimen-staining methods, imaging instrumentsincluding intermediate high-voltage transmission electron microscopes (IVEMs) and high-speed, large-format laser-scanning light microscopesand computational capabilities are available for addressing mesoscale biological microscopy of proteins and macromolecular complexes in their cellular and tissue environments. These technologies are developed to bridge understanding of biological systems between the gross anatomical and molecular scales and to make these technologies broadly available to biomedical researchers. NCMIR provides expertise, infrastructure, technological development, and an environment in which new information about the 3D ultrastructure of tissues, cells, and macromolecular complexes may be accurately and easily obtained and analyzed. NCMIR fulfills its mission through technology development, collaboration, service, training, and dissemination. It aims to develop preparative methods and analytical approaches to 3D microscopy applicable to neurobiology and cell biology, incorporating equipment and implementing software that expand the analysis of 3D structure. The core research activities in the areas of specimen development, instrument development, and software infrastructures maximize the advantages of higher voltage electron microscopy and correlated light microscopies to make ambitious imaging studies across scales routine, and to facilitate the use of resources by biomedical researchers. NCMIR actively recruits outside users who will not only make use of these resources, but who also will drive technology development and receive training.
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