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

Joana Fort, Laura R. de la Ballina, Hans E. Burghardt, Carles Ferrer-Costa, Javier Turnay, Cristina Ferrer-Orta, Isabel Usón, Antonio Zorzano, Juan Fernández-Recio, Modesto Orozco, María Antonia Lizarbe, Ignacio Fita (+1 others)
2007 Journal of Biological Chemistry  
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
more » ... ytic residues and consequently catalytic activity. 2DH3 is a dimer with Zn 2؉ coordination at the interface. Human 4F2hc expressed in several cell types resulted in cell surface and Cys 109 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 Cys 109 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 Cys 109intervening 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. 4 The abbreviations used are: HAT, heteromeric amino acid transporter; PDB, Protein Data
doi:10.1074/jbc.m704524200 pmid:17724034 fatcat:2zivgwhpa5hj3ddekzzfnecct4