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J. Biol. Chem., Vol. 281, Issue 32, 22896-22905, August 11, 2006

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Crystal Structure of the Second LNS/LG Domain from Neurexin 1

Ca²⁺ BINDING AND THE EFFECTS OF ALTERNATIVE SPLICING^*

Lauren R. Sheckler, Lisa Henry, Shuzo Sugita^¶, Thomas C. Südhof^¶, and Gabby Rudenko¹

From the Life Sciences Institute and Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109-2216 and the Department of Biochemistry and the ^¶Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Howard Hughes Medical Institute, Dallas, Texas 75390-9111

Neurexins mediate protein interactions at the synapse, playing an essential role in synaptic function. Extracellular domains of neurexins, and their fragments, bind a distinct profile of different proteins regulated by alternative splicing and Ca²⁺. The crystal structure of n1_LNS#2 (the second LNS/LG domain of bovine neurexin 1) reveals large structural differences compared with n1_LNS#6 (or n1_LNS), the only other LNS/LG domain for which a structure has been determined. The differences overlap the so-called hyper-variable surface, the putative protein interaction surface that is reshaped as a result of alternative splicing. A Ca²⁺-binding site is revealed at the center of the hyper-variable surface next to splice insertion sites. Isothermal titration calorimetry indicates that the Ca²⁺-binding site in n1_LNS#2 has low affinity (K_d 400 µM). Ca²⁺ binding ceases to be measurable when an 8- or 15-residue splice insert is present at the splice site SS#2 indicating that alternative splicing can affect Ca²⁺-binding sites of neurexin LNS/LG domains. Our studies initiate a framework for the putative protein interaction sites of neurexin LNS/LG domains. This framework is essential to understand how incorporation of alternative splice inserts expands the information from a limited set of neurexin genes to produce a large array of synaptic adhesion molecules with potentially very different synaptic function.

Received for publication, April 11, 2006 , and in revised form, May 23, 2006.

The atomic coordinates and structure factors (code 2H0B) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the National Alliance for Research on Schizophrenia and Depression, the American Heart Association, and by the National Institute of Mental Health Grant R01MH077303. Synchrotron radiation at Cornell High Energy Synchrotron Source (CHESS) used for data collection was funded by the National Science Foundation under Grant DMR 0225180, using the Macromolecular Diffraction at CHESS (MacCHESS) facility, which was supported by award RR-01646 from the National Institutes of Health, through its National Center for Research Resources. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Life Sciences Institute, University of Michigan, 210 Washtenaw Ave., Rm. 3163A, Ann Arbor, MI 48109-2216. Tel.: 734-615-9323; Fax: 734-763-6492; E-mail: rudenko{at}umich.edu.

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