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J. Biol. Chem., Vol. 280, Issue 42, 35329-35336, October 21, 2005

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Multivalent Interactions of Calcium/Calmodulin-dependent Protein Kinase II with the Postsynaptic Density Proteins NR2B, Densin-180, and -Actinin-2^*

From the Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232-0615

Dendritic calcium/calmodulin-dependent protein kinase II (CaMKII) is dynamically targeted to the synapse. We show that CaMKII is associated with the CaMKII-binding proteins densin-180, the N-methyl-D-aspartate receptor NR2B subunit, and -actinin in postsynaptic density-enriched rat brain fractions. Residues 819-894 within the C-terminal domain of -actinin-2 constitute the minimal CaMKII-binding domain. Similar amounts of Thr²⁸⁶-autophosphorylated CaMKII holoenzyme [P-T²⁸⁶]CaMKII bind to -actinin-2 as bind to NR2B (residues 1260-1339) or to densin-180 (residues 1247-1495) in glutathione-agarose cosedimentation assays, even though the CaMKII-binding domains share no amino acid sequence similarity. Like NR2B, -actinin-2 binds to representative splice variants of each CaMKII gene (, , , and ), whereas densin-180 binds selectively to CaMKII. In addition, C-terminal truncated CaMKII monomers can interact with NR2B and -actinin-2, but not with densin-180. Soluble -actinin-2 does not compete for [P-T²⁸⁶]CaMKII binding to immobilized densin-180 or NR2B. However, soluble densin-180, but not soluble NR2B, increases CaMKII binding to immobilized -actinin-2 by 10-fold in a PDZ domain-dependent manner. A His₆-tagged NR2B fragment associates with GST-densin or GST-actinin but only in the presence of [P-T²⁸⁶]CaMKII. Similarly, His₆-tagged densin-180 or -actinin fragments associate with GST-NR2B in a [P-T²⁸⁶]CaMKII-dependent manner. In addition, GST-NR2B and His₆-tagged -actinin can bind simultaneously to monomeric CaMKII subunits. In combination, these data support a model in which [P-T²⁸⁶]CaMKII can simultaneously interact with multiple dendritic spine proteins, possibly stabilizing the synaptic localization of CaMKII and/or nucleating a multiprotein synaptic signaling complex.

Received for publication, February 25, 2005 , and in revised form, August 15, 2005.

^* This work was supported by National Institutes of Health Grants F32-MH068129, 5T32-DK07563, RO1-MH63232, and RO1-NS44282 and by the American Heart Association. 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: Dept. of Molecular Physiology and Biophysics, Vanderbilt University, 702 Light Hall, Nashville, TN 37232-0615. Tel.: 615-936-1630; Fax: 615-322-7236; E-mail: roger.colbran{at}vanderbilt.edu.

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