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J. Biol. Chem., Vol. 281, Issue 42, 31762-31769, October 20, 2006

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Specificity of the Myotubularin Family of Phosphatidylinositol-3-phosphatase Is Determined by the PH/GRAM Domain^*

Papiya Choudhury¹, Shekhar Srivastava¹, Zhai Li, Kyung Ko, Mamdouh Albaqumi^¶, Kartik Narayan^||, William A. Coetzee^**, Mark A. Lemmon^||, and Edward Y. Skolnik^¶2

From the Departments of Medicine and ^**Pediatric Cardiology, the ^¶Division of Nephrology, and The Skirball Institute, New York University School of Medicine, New York, New York 10016 and the ^||Department of Biochemistry and Biophysics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

Myotubularins (MTM) are a large subfamily of lipid phosphatases that specifically dephosphorylate at the D3 position of phosphatidylinositol 3-phosphate (PI(3)P) in PI(3)P and PI(3,5)P₂. We recently found that MTMR6 specifically inhibits the Ca²⁺-activated K⁺ channel, KCa3.1, by dephosphorylating PI(3)P. We now show that inhibition is specific for MTMR6 and other MTMs do not inhibit KCa3.1. By replacing either or both of the coiled-coil (CC) and pleckstrin homology/GRAM (PH/G) domains of MTMs that failed to inhibit KCa3.1 with the CC and PH/G domains of MTMR6, we found that chimeric MTMs containing both the MTMR6 CC and PH/G domains functioned like MTMR6 to inhibit KCa3.1 channel activity, whereas chimeric MTMs containing either domain alone did not. Immunofluorescent microscopy demonstrated that both the MTMR6 CC and PH/G domains are required to co-localize MTMR6 to the plasma membrane with KCa3.1. These findings support a model in which two specific low affinity interactions are required to co-localize MTMR6 with KCa3.1: 1) between the CC domains on MTMR6 and KCa3.1 and (2) between the PH/G domain and a component of the plasma membrane. Our inability to detect significant interaction of the MTMR6 G/PH domain with phosphoinositides suggests that this domain may bind a protein. Identifying the specific binding partners of the CC and PH/G domains on other MTMs will provide important clues to the specific functions regulated by other MTMs as well as the mechanism(s) whereby loss of some MTMs lead to disease.

Received for publication, July 3, 2006 , and in revised form, August 1, 2006.

^* 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.

¹ Co-first authors.

² To whom correspondence should be addressed: The Skirball Inst., New York University School of Medicine, 540 First Ave., New York, NY 10016. Tel.: 212-263-7458; Fax: 212-263-8951; E-mail: Skolnik{at}saturn.med.nyu.edu.

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