Article ; Online: Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1.
The Journal of biological chemistry
2015 Volume 291, Issue 11, Page(s) 5788–5802
Abstract: 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. ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Cells, Cultured ; Contactin 1/metabolism ; HEK293 Cells ; Hippocampus/cytology ; Hippocampus/metabolism ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Membrane Proteins/ultrastructure ; Mice, Inbred C57BL ; Models, Molecular ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/ultrastructure ; Protein Interaction Maps ; Protein Structure, Tertiary ; Scattering, Small Angle ; X-Ray Diffraction |
| Chemical Substances | CNTN1 protein, human ; CNTNAP2 protein, human ; Contactin 1 ; Membrane Proteins ; Nerve Tissue Proteins |
| Language | English |
| Publishing date | 2015-12-31 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2997-x |
| ISSN | 1083-351X ; 0021-9258 |
| ISSN (online) | 1083-351X |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M115.705681 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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