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The Journal of Neuroscience, February 15, 1999, 19(4):1307-1316

Molecular Analysis of the X11-mLin-2/CASK Complex in Brain

Jean-Paul Borg¹, Manuel O. Lõpez-Figueroa⁴, Mylène de Taddèo-Borg², Dallas E. Kroon¹, R. Scott Turner³, Stanley J. Watson⁴, and Ben Margolis^{1, 2}

¹ Howard Hughes Medical Institute, Departments of ² Internal Medicine and ³ Neurology and Biological Chemistry, ⁴ Mental Health Research Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109

A heterotrimeric complex containing Lin-10/X11, Lin-2/CASK, and Lin-7 is evolutionarily conserved from worms to mammals. In Caenorhabditis elegans, it localizes Let-23, a receptor tyrosine kinase, to the basolateral side of vulval epithelium, a step crucial for proper vulva development. In mammals, the complex may also participate in receptor targeting in neurons. Accordingly, phosphotyrosine binding (PTB) and postsynaptic density-95/Discs large/Zona Occludens-1 domains found in X11 and mLin-2/CASK bind to cell-surface proteins, including amyloid precursor protein, neurexins, and syndecans. In this paper, we have further analyzed the X11-mLin-2/CASK association that is mediated by a novel protein-protein interaction. We show that the mLin-2/CASK calmodulin kinase II (CKII) domain directly binds to a 63 amino acids peptide located between the Munc-18-1 binding site and the PTB domain in X11. Ca²⁺/calmodulin association with mLin-2/CASK does not modify the X11-mLin-2 interaction. A region containing the mLin-2/CASK guanylate kinase domain also interacts with X11 but with a lower affinity than the CKII domain. Immunostaining of X11 in the brain shows that the protein is expressed in areas shown previously to be positive for mLin-2/CASK staining. Together, our data demonstrate that the X11-mLin-2 complex contacts many partners, creating a macrocomplex suitable for receptor targeting at the neuronal plasma membrane.

Key words: PDZ; PTB; X11; mLin-2/CASK; CaM kinase; receptor localization

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1941307-10$05.00/0

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