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J. Biol. Chem., Vol. 280, Issue 18, 18245-18252, May 6, 2005

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Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein^*

Thierry C. Aupérin¶, Gilles R. Bolduc||, Miriam J. Baron||, Annie Heroux**, David J. Filman, Lawrence C. Madoff||, and James M. Hogle

From the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, the ^||Brigham and Women's Hospital, Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, and the ^**Biology Department, 463, Brookhaven National Laboratory, Upton, New York 11973-5000

Group B Streptococcus (GBS) is the leading cause of bacterial pneumonia, sepsis, and meningitis among neonates and an important cause of morbidity among pregnant women and immunocompromised adults. Invasive diseases due to GBS are attributed to the ability of the pathogen to translocate across human epithelial surfaces. The alpha C protein (ACP) has been identified as an invasin that plays a role in internalization and translocation of GBS across epithelial cells. The soluble N-terminal domain of ACP (NtACP) blocks the internalization of GBS. We determined the 1.86-Å resolution crystal structure of NtACP comprising residues Ser⁵² through Leu²²⁵ of the full-length ACP. NtACP has two domains, an N-terminal -sandwich and a C-terminal three-helix bundle. Structural and topological alignments reveal that the -sandwich shares structural elements with the type III fibronectin fold (FnIII), but includes structural elaborations that make it unique. We have identified a potential integrin-binding motif consisting of Lys-Thr-Asp¹⁴⁶, Arg¹¹⁰, and Asp¹¹⁸. A similar arrangement of charged residues has been described in other invasins. ACP shows a heparin binding activity that requires NtACP. We propose a possible heparin-binding site, including one surface of the three-helix bundle, and nearby portions of the sandwich and repeat domains. We have validated this prediction using assays of the heparin binding and cell-adhesion properties of engineered fragments of ACP. This is the first crystal structure of a member of the highly conserved Gram-positive surface alpha-like protein family, and it will enable the internalization mechanism of GBS to be dissected at the atomic level.

Received for publication, November 2, 2004 , and in revised form, February 25, 2005.

The atomic coordinates and structure factors (code 1YWM) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported by Public Health Services Grant AI38424 (to L. C. M.) and the William Randolph Hearst Fund (to G. R. B.). 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.

Both authors contributed equally to this work.

^¶ Current address: Dept. of Biological Sciences, Columbia University, 703 Fairchild Center, M.C. 2452, 1212 Amsterdam Ave., New York, NY 10027.

To whom correspondence should be addressed: Harvard Medical School, Dept. of Biological Chemistry and Molecular Pharmacology, 240 Longwood Ave., Boston, MA 02115. Tel.: 617-432-3918; Fax: 617-432-4360; E-mail: jhogle{at}hms.harvard.edu.

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