Molecular architecture of contactin-Associated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2)

Zhuoyang Lu, M. V V V Sekhar Reddy, Jianfang Liu, Ana Kalichava, Jiankang Liu, Lei Zhang, Fang Chen, Yun Wang, Luis Marcelo F Holthauzen, Mark White, Suchithra Seshadrinathan, Xiaoying Zhong, Gang Ren, Gabrielle Rudenko

Research output: Contribution to journalArticle

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Abstract

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 arenot 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.

Original languageEnglish (US)
Pages (from-to)24133-24147
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number46
DOIs
StatePublished - Nov 11 2016

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Contactin 2
Contactins
Proteins
Language Development Disorders
Molecules
Nervous System Diseases
Neuroglia
Intellectual Disability
Adhesives
Labeling
Electron microscopy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Molecular architecture of contactin-Associated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2). / Lu, Zhuoyang; Reddy, M. V V V Sekhar; Liu, Jianfang; Kalichava, Ana; Liu, Jiankang; Zhang, Lei; Chen, Fang; Wang, Yun; Holthauzen, Luis Marcelo F; White, Mark; Seshadrinathan, Suchithra; Zhong, Xiaoying; Ren, Gang; Rudenko, Gabrielle.

In: Journal of Biological Chemistry, Vol. 291, No. 46, 11.11.2016, p. 24133-24147.

Research output: Contribution to journalArticle

Lu, Z, Reddy, MVVVS, Liu, J, Kalichava, A, Liu, J, Zhang, L, Chen, F, Wang, Y, Holthauzen, LMF, White, M, Seshadrinathan, S, Zhong, X, Ren, G & Rudenko, G 2016, 'Molecular architecture of contactin-Associated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2)', Journal of Biological Chemistry, vol. 291, no. 46, pp. 24133-24147. https://doi.org/10.1074/jbc.M116.748236
Lu, Zhuoyang ; Reddy, M. V V V Sekhar ; Liu, Jianfang ; Kalichava, Ana ; Liu, Jiankang ; Zhang, Lei ; Chen, Fang ; Wang, Yun ; Holthauzen, Luis Marcelo F ; White, Mark ; Seshadrinathan, Suchithra ; Zhong, Xiaoying ; Ren, Gang ; Rudenko, Gabrielle. / Molecular architecture of contactin-Associated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2). In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 46. pp. 24133-24147.
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