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J. Biol. Chem., Vol. 283, Issue 5, 2761-2772, February 1, 2008

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Conformational Rearrangement within the Soluble Domains of the CD4 Receptor Is Ligand-specific^*

Ashish, Ignacio J. Juncadella, Renu Garg^¶, Christopher D. Boone, Juan Anguita¹, and Joanna K. Krueger²

From the Departments of Chemistry and ^¶Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223 and the Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, Massachusetts 01003

Ligand binding induces shape changes within the four modular ectodomains (D1–D4) of the CD4 receptor, an important receptor in immune signaling. Small angle x-ray scattering (SAXS) on both a two-domain and a four-domain construct of the soluble CD4 (sCD4) is consistent with known crystal structures demonstrating a bilobal and a semi-extended tetralobal Z conformation in solution, respectively. Detection of conformational changes within sCD4 as a result of ligand binding was followed by SAXS on sCD4 bound to two different glycoprotein ligands: the tick saliva immunosuppressor Salp15 and the HIV-1 envelope protein gp120. Ab initio modeling of these data showed that both Salp15 and gp120 bind to the D1 domain of sCD4 and yet induce drastically different structural rearrangements. Upon binding, Salp15 primarily distorts the characteristic lobal architecture of the sCD4 without significantly altering the semi-extended shape of the sCD4 receptor. In sharp contrast, the interaction of gp120 with sCD4 induces a shape change within sCD4 that can be described as a Z-to-U bi-fold closure of the four domains across its flexible D2–D3 linker. Placement of known crystal structures within the boundaries of the SAXS-derived models suggests that the ligand-induced shape changes could be a result of conformational changes within this D2–D3 linker. Functionally, the observed shape changes in CD4 receptor causes dissociation of lymphocyte kinase from the cytoplasmic domain of Salp15-bound CD4 and facilitates an interaction between the exposed V3 loops of CD4-bound gp120 molecule to the extracellular loops of its co-receptor, a step essential for HIV-1 viral entry.

Received for publication, October 9, 2007 , and in revised form, November 16, 2007.

^* This work was supported by National Science Foundation Career Award Grant MCB-0237676 (to J. K. K.), National Institutes of Health Grant AI053064 (to J. A.), and the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences Contract DE-AC02-98CH10886. 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 To whom correspondence may be addressed: Dept. of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA 01003. Tel.: 413-577-3317; Fax: 413-545-6326; E-mail: janguita{at}vasci.umass.edu. ² To whom correspondence may be addressed: Dept. of Chemistry, University of North Carolina at Charlotte, Charlotte, NC 28223. Tel.: 704-687-4913; Fax: 704-687-3151; E-mail: jkkruege{at}uncc.edu.

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