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J. Biol. Chem., Vol. 283, Issue 8, 5004-5013, February 22, 2008

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Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

A PUTATIVE Ca²⁺ MODULATOR MATURES HUMAN HAIR CUTICLE^*

Kenji Kizawa¹, Hidenari Takahara, Heinz Troxler^¶, Peter Kleinert^¶, Urara Mochida, and Claus W. Heizmann^¶

From the Basic Research Laboratory, Kanebo Cosmetics Inc., 5-3-28 Kotobuki-cho, Odawara 250-0002, Japan, the Department of Applied Biological Resource Sciences, School of Agriculture, Ibaraki University, Ami-machi, Inashiki-gun, Ibaraki 300-0393, Japan, and the ^¶Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland

S100A3 is a unique member of the Ca²⁺-binding S100 protein family with the highest cysteine content and affinity for Zn²⁺. This protein is highly expressed in the differentiating cuticular cells within the hair follicle and organized into mature hair cuticles. Previous studies suggest a close association of S100A3 with epithelial differentiation, leading to hair shaft formation, but its molecular function is still unknown. By two-dimensional PAGE-Western blot analyses using a modified citrulline antibody, we discovered that more than half of the arginine residues of native S100A3 are progressively converted to citrullines by Ca²⁺-dependent peptidylarginine deiminases. Confocal immunofluorescent microscopy showed that the cytoplasmic S100A3 within the cuticular layer is mostly co-localized with the type III isoform of peptidylarginine deiminase (PAD3) but not with PAD1. Recombinant PAD1 and PAD2 are capable of converting all 4 arginines in recombinant S100A3, whereas PAD3 specifically converts only Arg-51 into citrulline. Gel filtration analyses showed that either enzymatic conversion of Arg-51 in S100A3 to citrulline or its mutational substitution with alanine (R51A) promotes a homotetramer assembly. Fluorescent titration of R51A suggested that its potential Ca²⁺ binding property increased during tetramerization. A prototype structural model of the globular Ca²⁺-bound S100A3 tetramer with citrulline residues is presented. High concentrations of S100A3 homotetramer might provide the millimolar level of Ca²⁺ required for hair cuticular barrier formation.

Received for publication, November 14, 2007

^* 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 method and Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 81-465-34-6116; Fax: 81-465-34-3037; E-mail: kizawa.kenji{at}kanebocos.co.jp.

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