Group of structural immunology

The research projects are developed around the following two main topics

• Structural studies of innate immune proteins (in close collaboration with IBS/LEM).
• Structural studies of the TCR receptors (cross reactivity, alloreactivity, structural basis of immunogenicity).

Structural studies of innate immune proteins

Contacts : C.Gaboriaud

Objectives : To solve and analyse protein structures and their complexes in order to decipher the molecular mechanisms involved in the very early steps of innate immunity. This includes the definition of the structural bases for the recognition by innate immune proteins of pathogens or aptotic cells or abnormal forms of proteins from self. These structural studies are performed in close collaboration with the ’innate immune’ team of IBS/LEM (see also on this web site their description and image gallery , which mostly includes the structures solved here).

Innate immune proteins : Innate immunity provides the front line of defence against infection, through the concerted action of a variety of recognition molecules that include both soluble proteins and membrane receptors. Some of the soluble recognition proteins have developed the ability to associate to proteases and are thus able to trigger defence reactions in response to pathogen recognition. Thus, the C1q protein associates to proteases C1r and C1s to form the C1 complex that is responsible for triggering the classical pathway of complement, a major system of innate immunity. Other examples are mannan-binding lectin (MBL) and the L- and H-ficolins. These oligomeric lectins recognize oligosaccharide patterns at the surface of pathogens and trigger the lectin pathway of complement through the action of the proteases (MBL-associated proteases, or MASPs) to which they associate. Our objective is to elucidate the structure and decipher the mechanism of action of the C1 and MBL-MASP or ficolin-MASP complexes. More insights into the interactions of C1q, MBL and ficolins with their cellular receptors will be addressed in the future, such as the consequences of the direct interaction of some pathogens with these molecules.

Topics

• Proteins of innate immunity : structure and function of the proteolytic complexes that trigger the classical and lectin pathways of complement
• Structural basis of the innate recognition properties of the ficolins
• Structural basis of the various recognition properties of the C1q subunit of the C1 complex, including the recognition of apoptotic cells and the pathologic form of the prion protein.

Key words

Innate immunity - Complement - Molecular recognition - Serine proteases - Prion protein - Amyloid fibrils - Apoptotic cells - Phagocytosis - Host pathogen interactions.

Specialized techniques

Crystallization, X-ray diffraction, protein structure analysis

Outstanding publications:

Païdassi H., Tacnet-Delorme P., Garlatti V., Darnault C., Ghebrehiwet B., Gaboriaud C., Arlaud G.J., Frachet P. (2008) C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J. Immunol. 180, 2329-2338.

Garlatti V., Martin L., Gout E., Reiser J.B., Fujita T., Arlaud G.J., Thielens N.M., Gaboriaud C. (2007) Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J. Biol. Chem. 282, 35831-35841.

Arlaud G.J., Barlow P.N., Gaboriaud C., Gros P., Narayana S.V. (2007) Deciphering complement mechanisms: the contributions of structural biology. Mol. Immunol. 44, 3809-3822.

Garlatti V., Belloy N., Martin L., Lacroix M., Matsushita M., Endo Y., Fujita T., Fontecilla-Camps J.C., Arlaud G. J., Thielens N. M., Gaboriaud C. (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J. 26, 623-633.

Gaboriaud C., Thielens N. M., Gregory L. A., Rossi V., Fontecilla-Camps J. C. and Arlaud G. J (2004) Structure and activation of the C1 complex of complement: unravelling the puzzle. Trends in Immunol. 25, 368-373.

Gregory L. A., Thielens N. M., Matsushita M., Sorensen R., Arlaud G. J., Fontecilla-Camps J. C. & Gaboriaud C. (2004) The X-ray structure of human Mannan-binding lectin- Associated protein 19 (MAp19) and its interaction site with Mannan-binding Lectin and L-ficolin, J. Biol. Chem. 279, 29391-29397

Gaboriaud C., Juanhuix J., Gruez A., Lacroix M., Darnault C., Pignol D., Verger D., Fontecilla-Camps J.C. & Arlaud G.J. (2003) The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J. Biol. Chem. 278, 46974-46982.

Budayova-Spano M., Lacroix M., Thielens N. M., Arlaud G. J., Fontecilla-Camps J. C. & Gaboriaud C. (2002) The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex. EMBO J. 21, 231-239.

Gaboriaud C., Rossi V., Bally I., Arlaud G. J. & Fontecilla-Camps J. C. (2000) Crystal structure of the catalytic domain of human complement C1s: a serine protease with a handle. EMBO J. 19, 1755-1765.

Biologie structurale des protéines de l’immunité

Please read the french version.