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J. Biol. Chem., Vol. 282, Issue 43, 31444-31452, October 26, 2007

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The Structure of Human 4F2hc Ectodomain Provides a Model for Homodimerization and Electrostatic Interaction with Plasma Membrane^*

Joana Fort¹, Laura R. de la Ballina¹, Hans E. Burghardt, Carles Ferrer-Costa^¶, Javier Turnay^||, Cristina Ferrer-Orta, Isabel Usón^**, Antonio Zorzano, Juan Fernández-Recio^¶, Modesto Orozco^¶, María Antonia Lizarbe^||, Ignacio Fita², and Manuel Palacín³

From the Institute for Research in Biomedicine, Barcelona Science Park and the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras, E-08028 Barcelona, the Instituto de Biología Molecular de Barcelona (Consejo Superior de Investigaciones Científicas), Institute for Research in Biomedicine, Barcelona Science Park, Barcelona E-08028, ^¶Molecular Modeling and Bioinformatics, Institute for Research in Biomedicine, Barcelona E-08028, the ^||Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, ^**ICREA at Instituto de Biología Molecular de Barcelona (Consejo Superior de Investigaciones Científicas), E-08028 Barcelona, and Barcelona Supercomputing Center, E-08028 Barcelona, Spain

4F2hc (CD98hc) is a multifunctional type II membrane glycoprotein involved in amino acid transport and cell fusion, adhesion, and transformation. The structure of the ectodomain of human 4F2hc has been solved using monoclinic (Protein Data Bank code 2DH2) and orthorhombic (Protein Data Bank code 2DH3) crystal forms at 2.1 and 2.8 Å, respectively. It is composed of a ()₈ barrel and an antiparallel ₈ sandwich related to bacterial -glycosidases, although lacking key catalytic residues and consequently catalytic activity. 2DH3 is a dimer with Zn²⁺ coordination at the interface. Human 4F2hc expressed in several cell types resulted in cell surface and Cys¹⁰⁹ disulfide bridge-linked homodimers with major architectural features of the crystal dimer, as demonstrated by cross-linking experiments. 4F2hc has no significant hydrophobic patches at the surface. Monomer and homodimer have a polarized charged surface. The N terminus of the solved structure, including the position of Cys¹⁰⁹ residue located four residues apart from the transmembrane domain, is adjacent to the positive face of the ectodomain. This location of the N terminus and the Cys¹⁰⁹-intervening disulfide bridge imposes space restrictions sufficient to support a model for electrostatic interaction of the 4F2hc ectodomain with membrane phospholipids. These results provide the first crystal structure of heteromeric amino acid transporters and suggest a dynamic interaction of the 4F2hc ectodomain with the plasma membrane.

Received for publication, June 1, 2007 , and in revised form, July 26, 2007.

The atomic coordinates and structure factors (code 2DH2 and 2DH3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the Spanish Ministry of Science and Education Grant SAF2003-08940, BFU2006-14600, and BIO2005-06753, by the EC Project Grant 502802 EUGINDAT, and by La Marató-TV3. 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 Materials and Methods, additional references, Figs. 1–8, and Table 1.

¹ Both authors should be considered first authors. Recipients of a predoctoral fellowship from the Spanish Ministry of Science and Education.

² To whom correspondence may be addressed. Tel.: 34-934034949; E-mail: ifrcri{at}ibmb.csic.es. ³ To whom correspondence may be addressed. Tel.: 34-934037199; E-mail: mpalacin{at}pcb.ub.es.

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