Ziel
The ubiquitous FIC domain catalyzes post-translational modifications (PTMs) of target proteins; i.e.
adenylylation (=AMPylation) and, more rarely, uridylylation and phosphocholination. Fic proteins are
thought to play critical roles in intrinsic signaling processes of prokaryotes and eukaryotes; however, a
subset encoded by bacterial pathogens is translocated via dedicated secretion systems into the cytoplasm of
mammalian host cells. Some of these host-targeted Fic proteins modify small GTPases leading to collapse of
the actin cytoskeleton and other drastic cellular changes. Recently, we described a large set of functionally
diverse homologues in pathogens of the genus Bartonella that are required for their “stealth attack” strategy
and persistent course of infection [1, 2]. Our preliminary functional analysis of some of these host-targeted
Fic proteins of Bartonella demonstrated adenylylation activity towards novel host targets (e.g. tubulin and
vimentin). Moreover, in addition to the canonical adenylylation activity they may also display a competing
kinase activity resulting from altered ATP binding to the FIC active site. Finally, we described a conserved
mechanism of FIC active site auto- inhibition that is relieved by a single amino acid exchange [1], thus
facilitating functional analysis of any Fic protein of interest. Despite this recent progress only a few Fic
proteins have been functionally characterized to date; our understanding of the functional plasticity of the
FIC domain in mediating diverse target PTMs and their specific roles in infection thus remains limited.
In this project, we aim to study the vast repertoire of host-targeted Fic proteins of Bartonella to: 1)
identify novel target proteins and types of PTMs; 2) study their physiological consequences and molecular
mechanisms of action; and 3) analyze structure-function relationships critical for FIC-mediated PTMs and infer from these data determinants of target specificity, type of PTM and mode of regulation. At the forefront of infection biology research, this project is ground-breaking as (i) we will identify a
plethora of novel host target PTMs that are critical for a “stealth attack” infection strategy and thus will open
new avenues for investigating fundamental mechanisms of persistent infection; and (ii), we will unveil the
molecular basis of the remarkable functional versatility of the structurally conserved FIC domain.
Wissenschaftliches Gebiet
Aufforderung zur Vorschlagseinreichung
ERC-2013-ADG
Andere Projekte für diesen Aufruf anzeigen
Finanzierungsplan
ERC-AG - ERC Advanced GrantGastgebende Einrichtung
4051 Basel
Schweiz