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J. Biol. Chem., Vol. 281, Issue 37, 27539-27556, September 15, 2006

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Titin as a Giant Scaffold for Integrating Stress and Src Homology Domain 3-mediated Signaling Pathways

THE CLUSTERING OF NOVEL OVERLAP LIGAND MOTIFS IN THE ELASTIC PEVK SEGMENT^*

From the Muscle Proteomics and Nanotechnology Section, Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, Maryland 20892

The richness of proline sequences in titins qualifies these giant proteins as the largest source of intrinsically disordered structures in nature. An extensive search and analysis for Src homology domain 3 (SH3) ligand motifs revealed a myriad of broadly distributed SH3 ligand motifs, with the highest density in the PEVK segments of human titin. Besides the canonical class I and II motifs with opposite orientations, novel overlapping motifs consisting of one or more of each canonical motif are abundant. Experimentally, the binding affinity and critical residues of these putative titin-based SH3 ligands toward nebulin SH3 and other SH3-containing proteins in muscle and non-muscle cell extracts were validated with peptide array technology and by the sarcomere distribution of SH3-containing proteins. A 28-mer overlapping motif-containing PEVK module binds to nebulin SH3 in and around the canonical cleft, especially to the acidic residues in the loops, as revealed by NMR titration. Molecular dynamics and molecular docking studies indicated that the overlapping motif can bind in opposite orientations with comparable energy and contact areas and predicts correctly orientation-specific contacts in NMR data. We propose that the overlap ligand motifs are a new class of ligands with innate ability to dictate SH3 domain orientation and to facilitate the rate, strength, and stereospecificity of receptor interactions. Proline-rich sequences of titins are candidates as major hubs of SH3-dependent signaling pathways. The interplay of elasticity and dense clustering of mixed receptor orientations in titin PEVK segment have important implications for the mechanical sensing, force sensitivity, and inter-adapter interactions in signaling pathways.

Received for publication, May 11, 2006

^* This work was supported by the Intramural Research Program of the NIAMS, National Institutes of Health, Department of Health and Human Services. 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. SF1 and Tables ST1 and ST2.

¹ Both authors contributed equally to this work.

² Present address: Institute of Chemical Biology and Drug Discovery, State University of New York, Stony Brook, NY 11794.

³ To whom correspondence should be addressed: Bldg. 50, Rm. 1140, Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-4097; Fax: 301-402-8566; E-mail: wangk{at}exchange.nih.gov.

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