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J. Biol. Chem., Vol. 280, Issue 45, 37988-37994, November 11, 2005

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The Coiled-coil Domain Is Required for HS1 to Bind to F-actin and Activate Arp2/3 Complex^*

From the Department of Pathology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 20855

HS1 (hematopoietic lineage cell-specific protein 1), a substrate of protein tyrosine kinases in lymphocytes, binds to F-actin, and promotes Arp2/3 complex-mediated actin polymerization. However, the mechanism for the interaction between HS1 and F-actin has not yet been fully characterized. HS1 contains 3.5 tandem repeats, a coiled-coil region, and an SH3 domain at the C terminus. Unlike cortactin, which is closely related to HS1 and requires absolutely the repeat domain for F-actin binding, an HS1 mutant with deletion of the repeat domain maintains a significant F-actin binding activity. On the other hand, deletion of the coiled-coil region abolished the ability of HS1 to bind to actin filaments and to activate the Arp2/3 complex for actin nucleation and actin branching. Furthermore, a peptide containing the coiled-coil sequence only was sufficient for F-actin binding. Within cells overexpressing green fluorescent protein-tagged HS1 proteins, wild type HS1 co-localizes with cortical F-actin at the cell leading edge, whereas mutants with deletion of either the coiled-coil region or the repeat domain diffuse in the cytoplasm. Immunoprecipitation analysis reveals that the coiled-coil deletion mutant binds poorly to F-actin, whereas the mutant without the repeat domain fails to bind to both Arp2/3 complex and F-actin. These data suggest that the HS1 coiled-coil region acts synergistically with the repeat domain in the modulation of the Arp2/3 complex-mediated actin polymerization.

Received for publication, April 26, 2005 , and in revised form, August 30, 2005.

^* This work was supported by Grant HL52753 from the National Institutes of Health and Grant CA91984 from the NCI, National Institutes of Health (to X. Z.). 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 Current address: National Cancer Institute, Experimental Immunology Branch, Bethesda, MD 20892.

² Current address: Affiliated Hospital of Nantong Medical College, Nantong, China 216000.

³ Current address: National Cancer Institute, SAIC-Frederick, MD 21702.

⁴ To whom correspondence should be addressed: Dept. of Pathology, 800 W. Baltimore St., Baltimore, MD 21201. E-mail: xzhan{at}som.umaryland.edu.

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