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TitleMolecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2).
Journal, issue, pagesJ Biol Chem, Vol. 291, Issue 46, Page 24133-24147, Year 2016
Publish dateNov 11, 2016
AuthorsZhuoyang Lu / M V V V Sekhar Reddy / Jianfang Liu / Ana Kalichava / Jiankang Liu / Lei Zhang / Fang Chen / Yun Wang / Luis Marcelo F Holthauzen / Mark A White / Suchithra Seshadrinathan / Xiaoying Zhong / Gang Ren / Gabby Rudenko /
PubMed AbstractContactin-associated protein-like 2 (CNTNAP2) is a large multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum ...Contactin-associated protein-like 2 (CNTNAP2) is a large multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, intellectual disability, and language delay. We reveal here by electron microscopy that the architecture of CNTNAP2 is composed of a large, medium, and small lobe that flex with respect to each other. Using epitope labeling and fragments, we assign the F58C, L1, and L2 domains to the large lobe, the FBG and L3 domains to the middle lobe, and the L4 domain to the small lobe of the CNTNAP2 molecular envelope. Our data reveal that CNTNAP2 has a very different architecture compared with neurexin 1α, a fellow member of the neurexin superfamily and a prototype, suggesting that CNTNAP2 uses a different strategy to integrate into the synaptic protein network. We show that the ectodomains of CNTNAP2 and contactin 2 (CNTN2) bind directly and specifically, with low nanomolar affinity. We show further that mutations in CNTNAP2 implicated in autism spectrum disorder are not segregated but are distributed over the whole ectodomain. The molecular shape and dimensions of CNTNAP2 place constraints on how CNTNAP2 integrates in the cleft of axo-glial and neuronal contact sites and how it functions as an organizing and adhesive molecule.
External linksJ Biol Chem / PubMed:27621318 / PubMed Central
MethodsEM (tomography) / EM (single particle)
Resolution12.0 - 20.0 Å
Structure data

EMDB-6717:
Contactin-2 reconstructed by Individual-Particle Electron Tomography
Method: EM (tomography) / Resolution: 20.0 Å

EMDB-9543:
IPET 3D reconstruction of an single CNTNAP2-antibody complex: conformation #1
Method: EM (tomography) / Resolution: 16.3 Å

EMDB-9544:
IPET 3D reconstruction of a single CNTNAP2-antibody complex: conformation #2
Method: EM (tomography) / Resolution: 16.3 Å

EMDB-9545:
Single particle reconstruction of CNTNAP2: conformation #7
Method: EM (single particle) / Resolution: 15.6 Å

EMDB-9546:
Single particle reconstruction of CNTNAP2: conformation #8
Method: EM (single particle) / Resolution: 15.7 Å

EMDB-9547:
IPET 3D reconstruction of a single CNTNAP2 - 1.8 nm nanogold complex
Method: EM (tomography) / Resolution: 14.6 Å

EMDB-9548:
IPET 3D reconstruction of a single CNTNAP2 - 5 nm nanogold complex
Method: EM (tomography) / Resolution: 12.0 Å

EMDB-9549:
IPET 3D reconstruction of a single CNTNAP2-C2 domain
Method: EM (tomography) / Resolution: 20.0 Å

EMDB-9550:
Single particle reconstruction of CNTNAP2: conformation #6
Method: EM (single particle) / Resolution: 17.0 Å

EMDB-9551:
Single particle reconstruction of CNTNAP2: conformation #5
Method: EM (single particle) / Resolution: 16.4 Å

EMDB-9552:
Single particle reconstruction of CNTNAP2: conformation #4
Method: EM (single particle) / Resolution: 13.7 Å

EMDB-9553:
Single particle reconstruction of CNTNAP2: conformation #3
Method: EM (single particle) / Resolution: 15.9 Å

EMDB-9554:
Single particle reconstruction of CNTNAP2: conformation #2
Method: EM (single particle) / Resolution: 15.7 Å

EMDB-9555:
Single particle reconstruction of CNTNAP2: conformation #1
Method: EM (single particle) / Resolution: 15.3 Å

EMDB-9556:
IPET 3D reconstruction of a single CNTNAP2: conformation #8
Method: EM (tomography) / Resolution: 16.9 Å

EMDB-9557:
IPET 3D reconstruction of a single CNTNAP2: conformation #7
Method: EM (tomography) / Resolution: 17.0 Å

EMDB-9558:
IPET 3D reconstruction of a single CNTNAP2: conformation #6
Method: EM (tomography) / Resolution: 15.6 Å

EMDB-9559:
IPET 3D reconstruction of a single CNTNAP2: conformation #5
Method: EM (tomography) / Resolution: 16.0 Å

EMDB-9560:
IPET 3D reconstruction of a single CNTNAP2: conformation #4
Method: EM (tomography) / Resolution: 16.5 Å

EMDB-9561:
IPET 3D reconstruction of a single CNTNAP2: conformation #3
Method: EM (tomography) / Resolution: 17.5 Å

EMDB-9562:
IPET 3D reconstruction of a single CNTNAP2: conformation #2
Method: EM (tomography) / Resolution: 18.9 Å

EMDB-9563:
IPET 3D reconstruction of a single CNTNAP2: conformation #1
Method: EM (tomography) / Resolution: 16.3 Å

Source
  • Homo sapiens (human)

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