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J. Biol. Chem., Vol. 279, Issue 38, 40185-40193, September 17, 2004

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Ankyrin-B Targets ₂-Spectrin to an Intracellular Compartment in Neonatal Cardiomyocytes^*

Peter J. Mohler¶, Woohyun Yoon¶, and Vann Bennett¶||**

From the Howard Hughes Medical Institute and Departments of ^¶Cell Biology, ^||Biochemistry, and ^**Neurosciences, Duke University Medical Center, Durham, North Carolina 27710

Ankyrin-B is a spectrin-binding protein that is required for localization of inositol 1,4,5-trisphosphate receptor and ryanodine receptor in neonatal cardiomyocytes. This work addresses the interaction between ankyrin-B and ₂-spectrin in these cells. Ankyrin-B and ₂-spectrin are colocalized in an intracellular striated compartment overlying the M-line and distinct from T-tubules, sarcoplasmic reticulum, Golgi, endoplasmic reticulum, lysosomes, and endosomes. ₂-Spectrin is absent in ankyrin-B-null cardiomyocytes and is restored to a normal striated pattern by rescue with green fluorescent protein-220-kDa ankyrin-B. We identified two mutants (A1000P and DAR976AAA) located in the ZU5 domain which eliminate spectrin binding activity of ankyrin-B. Ankyrin-B mutants lacking spectrin binding activity are normally targeted but do not reestablish ₂-spectrin in ankyrin-B^+/- cardiomyocytes. However, both mutant forms of ankyrin-B are still capable of restoring inositol 1,4,5-trisphosphate receptor localization and normal contraction frequency of cardiomyocytes. Therefore, direct binding of ₂-spectrin to ankyrin-B is required for the normal targeting of ₂-spectrin in neonatal cardiomyocytes. In contrast, ankyrin-B localization and function are independent of ₂-spectrin. In summary, this work demonstrates that interaction between members of the ankyrin and -spectrin families previously established in erythrocytes and axon initial segments also occurs in neonatal cardiomyocytes with ankyrin-B and ₂-spectrin. This work also establishes a functional hierarchy in which ankyrin-B determines the localization of ₂-spectrin and operates independently of ₂-spectrin in its role in organizing membrane-spanning proteins.

Received for publication, June 1, 2004 , and in revised form, June 28, 2004.

^* This work was supported by the Howard Hughes Medical Institute and Johnson and Johnson. 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 Supplemental Fig. 1.

To whom correspondence should be addressed: Dept. of Cell Biology, Howard Hughes Medical Institute, Box 3892, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-3027; Fax:919-684-3590; E-mail: p.mohler{at}cellbio.duke.edu or v.bennett{at}cellbio.duke.edu.

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