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J. Biol. Chem., Vol. 283, Issue 23, 16187-16193, June 6, 2008

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Cortactin Adopts a Globular Conformation and Bundles Actin into Sheets^*

Nathan P. Cowieson¹, Gordon King, David Cookson, Ian Ross^¶, Thomas Huber^||, David A. Hume^||2, Bostjan Kobe^||3, and Jennifer L. Martin^||4

From the Institute for Molecular Bioscience and Australian Research Council (ARC) Special Research Centre for Functional and Applied Genomics, University of Queensland, Brisbane QLD 4072 Australia, the Australian Synchrotron, 800 Blackburn Road, VIC 3168, Australia, and the ^¶Cooperative Research Center for Chronic Inflammatory Diseases, ^||School of Molecular and Microbial Sciences, University of Queensland, Brisbane QLD 4072 Australia

Cortactin is a filamentous actin-binding protein that plays a pivotal role in translating environmental signals into coordinated rearrangement of the cytoskeleton. The dynamic reorganization of actin in the cytoskeleton drives processes including changes in cell morphology, cell migration, and phagocytosis. In general, structural proteins of the cytoskeleton bind in the N-terminal region of cortactin and regulatory proteins in the C-terminal region. Previous structural studies have reported an extended conformation for cortactin. It is therefore unclear how cortactin facilitates cross-talk between structural proteins and their regulators. In the study presented here, circular dichroism, chemical cross-linking, and small angle x-ray scattering are used to demonstrate that cortactin adopts a globular conformation, thereby bringing distant parts of the molecule into close proximity. In addition, the actin bundling activity of cortactin is characterized, showing that fully polymerized actin filaments are bundled into sheet-like structures. We present a low resolution structure that suggests how the various domains of cortactin interact to coordinate its array of binding partners at sites of actin branching.

Received for publication, October 30, 2007 , and in revised form, February 22, 2008.

^* This work was supported by an Australian Synchrotron Radiation Program Fellowship and Access to Major Research Facilities Program travel funding (to N. C.), an Australian Research Council (ARC) grant (to J. L. M. and B. K.), and a grant from the University of Queensland (to T. H. and B. K.). 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 a supplemental spreadsheet.

² Present address: The Roslin Institute, University of Edinburgh, UK.

³ An ARC Federation Fellow and a National Health and Medical Research Council (NHMRC) Honorary Research Fellow.

⁴ An NHMRC Senior Research Fellow.

¹ To whom correspondence should be addressed: Nathan P. Cowieson, Monash Centre for Synchrotron Science, Monash University, VIC 3800, Australia. Tel.: 61-3-9902-0117; Fax: 61-3-9905-3637; E-mail: nathan.cowieson{at}sync.monash.edu.Au.

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