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J. Biol. Chem., Vol. 283, Issue 19, 13035-13043, May 9, 2008

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Mast Cell and Monocyte Recruitment by S100A12 and Its Hinge Domain^*

Wei Xing Yan, Chris Armishaw¹, Jesse Goyette, Zheng Yang², Hong Cai, Paul Alewood, and Carolyn L. Geczy³

From the Centre for Infection and Inflammation Research, University of New South Wales, Sydney, New South Wales 2052, Australia and Institute for Molecular Biosciences, University of Queensland, Queensland 4072, Australia

S100A12 is expressed at sites of acute, chronic, and allergic inflammation. S100 proteins have regions of high sequence homology, but the "hinge" region between the conserved calcium binding domains is structurally and functionally divergent. Because the murine S100A8 hinge domain (mS100A8^42–55) is a monocyte chemoattractant whereas the human sequence (hS100A8^43–56) is inactive, we postulated that common hydrophobic amino acids within the S100A12 hinge sequence may be functional. The hinge domain, S100A12^38–53, was chemotactic for human monocytes and murine mast cells in vitro. S100A12^38–53 provoked an acute inflammatory response similar to that elicited by S100A12 in vivo and caused edema and leukocyte and mast cell recruitment. Circular dichroism studies showed that S100A12^38–53 had increased helical structure in hydrophobic environments. Mutations in S100A12^38–53 produced using an alanine scan confirmed that specific hydrophobic residues (I44A, I47A, and I53A) on the same face of the helix were critical for monocyte chemotaxis in vitro and generation of edema in vivo. In a hydrophobic environment such as the cell membrane, these critical residues would likely align on one face of an -helix to facilitate receptor interaction. Interaction is unlikely to occur via the receptor for advanced glycation end products but, rather, via a G-protein-coupled mechanism.

Received for publication, December 20, 2007 , and in revised form, February 6, 2008.

^* This work was supported by the National Health and Medical Research Council, Australia. 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 Present address: Torrey Pines Institute for Molecular Studies, 5775 N. Old Dixie Hwy, Fort Pierce, FL 34946.

² Present address: Dept. of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117510.

³ To whom correspondence should be addressed: Inflammatory Diseases Research Unit, University of New South Wales 2052, Australia. Tel.: 0061-2-9385-2777; Fax: 0061-2-9385-2706; E-mail: c.geczy{at}unsw.edu.au.

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