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J. Biol. Chem., Vol. 283, Issue 7, 3889-3903, February 15, 2008

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Structural Requirements for Multimerization of the Pathogen Receptor Dendritic Cell-specific ICAM3-grabbing Non-integrin (CD209) on the Cell Surface^*

Diego Serrano-Gómez¹², Elena Sierra-Filardi¹, Rocío T. Martínez-Nuñez, Esther Caparrós, Rafael Delgado, Mari Angeles Muñoz-Fernández^¶, María Antonia Abad^||, Jesús Jimenez-Barbero, Manuel Leal^||, and Angel L. Corbí³

From the Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, Madrid 28040, Laboratorio de Microbiología Molecular, Hospital Doce de Octubre, Madrid 28041, the ^¶Servicio de Inmunología, Hospital General Universitario Gregorio Marañón, Madrid 28007, and the ^||Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain

The myeloid C-type lectin dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN, CD209) recognizes oligosaccharide ligands on clinically relevant pathogens (HIV, Mycobacterium, and Aspergillus). Alternative splicing and genomic polymorphism generate DC-SIGN mRNA variants, which have been detected at sites of pathogen entrance and transmission. We present evidence that DC-SIGN neck variants are expressed on dendritic and myeloid cells at the RNA and protein levels. Structural analysis revealed that multimerization of DC-SIGN within a cellular context depends on the lectin domain and the number and arrangement of the repeats within the neck region, whose glycosylation negatively affects oligomer formation. Naturally occurring DC-SIGN neck variants differ in multimerization competence in the cell membrane, exhibit altered sugar binding ability, and retain pathogen-interacting capacity, implying that pathogen-induced cluster formation predominates over the basal multimerization capability. Analysis of DC-SIGN neck polymorphisms indicated that the number of allelic variants is higher than previously thought and that multimerization of the prototypic molecule is modulated in the presence of allelic variants with a different neck structure. Our results demonstrate that the presence of allelic variants or a high level of expression of neck domain splicing isoforms might influence the presence and stability of DC-SIGN multimers on the cell surface, thus providing a molecular explanation for the correlation between DC-SIGN polymorphisms and altered susceptibility to HIV-1 and other pathogens.

Received for publication, July 23, 2007 , and in revised form, November 26, 2007.

^* This work was supported in part by the Ministerio de Educación y Ciencia (Grants SAF2005-0021, AGL2004-02148-ALI, and GEN2003-20649-C06-01/NAC), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Spanish Network for the Research in Infectious Diseases, Grant REIPI RD06/0008), and Fundación para la Investigación y Prevención del SIDA en España (Grant FIPSE 36422/03) (to A. L. C.). 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 Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² Supported by a Formación de Profesorado Universitario predoctoral grant (AP2002-2151) from Ministerio de Educación y Ciencia (Spain).

³ To whom correspondence should be addressed. Tel.: 34-91-837-3112 (ext. 4376); Fax: 34-91-562-7518; E-mail: acorbi{at}cib.csic.es.

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