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¹ Division of Infectious Disease Control, Advanced Medical Research Center, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan
² Department of Cortical Function Disorders, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
³ Laboratory of Neurochemistry, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
⁴ Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan

Dystroglycan (DG) is a widely expressed, transmembrane glycoprotein complex that plays important roles by connecting the extracellular matrix to the cytoskeleton. The - and ß-DG subunits are produced by the cleavage of residues 653 and 654 of the precursor. To clarify the mechanisms involved in cleavage and subunit association, we performed a series of mutation analyses and made the following discoveries: (i) Disruption of the intramolecular disulfide bridge between Cys669 and Cys713 in ß-DG completely abolishes the cleavage, (ii) deletions in the loop region (669–713) and in the C-terminal region of -DG (550–645) abolish the cleavage, (iii) disruption of the disulfide bridge and deletions in the loop region deteriorate the - and ß-DG subunit association, and (iv) at the cleavage site, especially, positions P1' (Ser654) and P6' (Trp659) are critical. Thus, the critical role of the Cys669–Cys713 disulfide bridge formation is, most likely, to form a specific tertiary structure, in which the - and ß-DG domains interact and the cleavage site becomes susceptible to proteolytic reactions. The Cys669 and Cys713 pair is broadly conserved in vertebrates and in some invertebrates, suggesting that the disulfide bridge formation was established early in the evolution of DG.

^aPresent address: Department of Bacteriology, Iwate Medical University, 19-1 Uchimaru, Morioka-shi, Iwate 020-8505, Japan

^* Correspondence: E-mail: tanakat{at}med.nihon-u.ac.jp

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