Unlike cerebellin 1 (Cbln1), which bridges neurexin (Nrxn) receptors and delta-type glutamate receptors in a trans-synaptic triad, Cbln4 was reported to have no or weak binding for the receptors despite sharing similar to 70% sequence identity with Cbln1. Here, we report crystal structures of the homotrimers of the C1q domain of Cbln1 and Cbln4 at 2.2 and 2.3 angstrom resolution, respectively. Comparison of the structures suggests that the difference between Cbln1 and Cbln4 in GluD2 binding might be because of their sequence and structural divergence in loop CD. Surprisingly, we show that Cbln4 binds to Nrxn1 beta and forms a stable complex with the laminin, nectin, sex-hormone binding globulin (LNS) domain of Nrxn1 beta. Furthermore, the negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 angstrom resolution and that of the Cbln4/Nrxn1 beta complex at 19 angstrom resolution suggest that Nrxn1 beta binds to the N-terminal region of Cbln4, probably through strand beta 10 of the S4 insert.
[1]Univ Chinese Acad Sci, Chinese Acad Sci, Ctr Excellence Mol Cell Sci,State Key Lab Mol Bio, Inst Biochem & Cell Biol,Natl Ctr Prot Sci Shangh, 320 Yueyang Rd, Shanghai 200031, Peoples R China;
[2]Shanghai Univ, Sch Life Sci, 333 Nanchen Rd, Shanghai 200444, Peoples R China;
[3]ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;
[4]Chinese Acad Sci, Shanghai Sci Res Ctr, Shanghai 201204, Peoples R China;
[5]Fudan Univ, Collaborat Innovat Ctr Genet & Dev, 2005 Song Hu Rd, Shanghai 200438, Peoples R China;
[6]SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA
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