# Federal Institute for Neurobiology, Dept. of Neurochemistry and Molecular Biology, P.O.Box 1860, D-39008 Magdeburg, Germany, % Neurobiology Research Center, University of Alabama at Birmingham, 1719 Sixth Ave. S., Birmingham, AL. 35213-0021,
Different approaches towards the molecular characterization of junctional protein complexes have recently lead to the identification of several membrane-associated guanylate kinase homologs (MAGUKs), including the synapse associated proteins PSD-95/SAP90, SAP97/hdlg and SAP102, as well as the tight junction proteins ZO-1 and ZO-2 (for review see Kim, 1995). These mammalian MAGUKs are structurally related to DlgA, the Drosophila prototype of this protein family (Woods and Bryant, 1991), thereby sharing a common three-partite domain organization: three so-called PDZ- domains (also denoted as GLGF- or DHR repeats ) are followed by a SH3 domain and a region with similarity to yeast guanylate kinase.
A pivotal role of MAGUKs in the structural and functional organization of membrane specializations is indicated by several lines of evidence. For instance, various neuronally expressed MAGUKs can bind (via their first two PDZ domains) to neuronal NO-synthase and to the cytoplasmic tails of NMDA-type glutamate receptors and Shaker-type potassium channels; at least in the latter case, this binding may result in channel clustering (reviewed by Gomperts, 1996).
In Drosophila, loss of zygotic DlgA function causes neoplastic overgrowth of imaginal disc epithelia and hyperplastic growth within larval brains. Furthermore, dlg-1 mutant larvae exhibit ultrastructural defects at the subsynaptic reticulum of certain neuromuscular junctions (NMJs), consistent with the localization of DlgA at these postsynaptic membrane specialization in the wildtype situation (Lahey et al.,1994).
Regardless of their structural similarity, the mammalian MAGUKs are different with respect to tissue distribution and subcellular localization. This raises the question whether the various MAGUKs are functionally equivalent and to which extend DlgA function has been conserved in these proteins. We have found, that single splice variants of SAP97 and SAP102 exhibit rescue activity in dlg-1 mutants with respect to both, tumor suppression and neuronal function. This functional substitution goes along with subcellular distributions that widely mimic that of DlgA. In the course of this study, we have also elucidated additional aspects of DlgA function in the fly. In particular, DlgA activity was found to be necessary for establishing structurally intact motor nerve terminals.
Ref.:
Gomperts, S. N. (1996). Cell 84, 659-662.
Kim, S. K. (1995). Curr Opin Cell Biol 5, 772-778.
Lahey, T., Gorczyca, M., Jia X. X. and Budnik V. (1994). Neuron 13, 823-835.
Woods, D. F. and Bryant, P. J. (1991). Cell 66, 451-464.