title: Conformational states of a bacterial α2-macroglobulin resemble those of human complement C3.
abstract: α(2) macroglobulins (α(2)Ms) are broad-spectrum protease inhibitors that play essential roles in the innate immune system of eukaryotic species. These large, multi-domain proteins are characterized by a broad-spectrum bait region and an internal thioester, which, upon cleavage, becomes covalently associated to the target protease, allowing its entrapment by a large conformational modification. Notably, α(2)Ms are part of a larger protein superfamily that includes proteins of the complement system, such as C3, a multi-domain macromolecule which is also characterized by an internal thioester-carrying domain and whose activation represents the pivotal step in the complement cascade. Recently, α(2)M/C3-like genes were identified in a large number of bacterial genomes, and the Escherichia coli α(2)M homolog (ECAM) was shown to be activated by proteases. In this work, we have structurally characterized ECAM by electron microscopy and small angle scattering (SAXS) techniques. ECAM is an elongated, flexible molecule with overall similarities to C3 in its inactive form; activation by methylamine, chymotrypsin, or elastase induces a conformational modification reminiscent of the one undergone by the transformation of C3 into its active form, C3b. In addition, the proposed C-terminus of ECAM displays high flexibility and different conformations, and could be the recognition site for partner macromolecules. This work sheds light on a potential bacterial defense mechanism that mimics structural rearrangements essential for activation of the complement cascade in eukaryotes, and represents a possible novel target for the development of antibacterials.
authors.affiliation: Institut de Biologie Structurale, Université Grenoble I, Grenoble, France. andrea.dessen@ibs.fr
authors.forename: David
authors.initials: D
authors.lastname: Neves
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Estrozi
authors.forename: Viviana
authors.initials: V
authors.lastname: Job
authors.forename: Frank
authors.initials: F
authors.lastname: Gabel
authors.forename: Guy
authors.initials: G
authors.lastname: Schoehn
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D003176:Complement C3 / Q000737:chemistry* / Q000378:metabolism; D003179:Complement C3b / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D000511:alpha-Macroglobulins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D001426:Bacterial Proteins; D003176:Complement C3; D000511:alpha-Macroglobulins; D003179:Complement C3b