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J. Biol. Chem., Vol. 278, Issue 43, 42190-42199, October 24, 2003

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PDZ Domain-mediated Interaction of Interleukin-16 Precursor Proteins with Myosin Phosphatase Targeting Subunits^*

Norbert Bannert, Karin Vollhardt, Bakhtier Asomuddinov, Marion Haag, Herbert König¶, Stephen Norley, and Reinhard Kurth

From the Robert Koch-Institute, Nordufer 20, 13353 Berlin, Germany and ^¶Paul-Ehrlich-Institute, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany

The cytokine interleukin-16 is generated by posttranscriptional cleavage by caspase-3 of two large precursor isoforms. The smaller protein of 67 kDa (pro-IL-16) is expressed in cells of the immune system and contains three PDZ (postsynaptic density/disc large/zona occludens-1) domains, whereas the larger 141-kDa neuronal variant (npro-IL-16) has two additional PDZ domains in its N-terminal extension that interact with neuronal ion channels. Using the yeast two-hybrid approach we have identified three closely related myosin phosphatase targeting subunits, MYPT1, MYPT2, and MBS85, as binding partners of the IL-16 precursor proteins. These interactions were verified using pull-down assays, coimmunoprecipitations, and plasmon resonance experiments. Binding requires the intact PDZ2 domain of pro-IL-16 and highly related C-terminal regions in the ligands consisting of a short leucine zipper and an indispensable serine at the -1 position, suggesting a novel unconventional PDZ binding mode. Pro-IL-16 and the myosin phosphatase targeting subunits colocalize along actomyosin filaments and stress fibers in transfected COS-7 cells. By modulating and targeting the catalytic phosphatase subunit to its substrates, MYPT1, MYPT2, and MBS85 regulate various contractile processes in muscle and non-muscle cells. Our findings indicate an involvement of the IL-16 precursor molecules in myosin-based contractile processes, most likely in cell motility, providing a functional link to the chemotactic activity of the mature cytokine. Alternatively, an intracellular complex of npro-IL-16, ion channels, and components of myosin motors in neurons suggests a role in protein targeting.

Received for publication, June 24, 2003 , and in revised form, August 13, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY324389.

^* The work was supported by a Deutscher Akademischer Austauschdienst fellowship (to B. A.) and by a grant from the Heinz Kuthe-de Mouson Foundation (Bole, Switzerland) (to R. K.). 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.

To whom correspondence should be addressed. Tel.: 30-4547-2234; Fax: 30-4547-2914; E-mail: BannertN{at}rki.de.

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