PT - JOURNAL ARTICLE AU - Priyanka Dutta AU - A.S. Jijumon AU - Mohit Mazumder AU - Drisya Dileep AU - Asish K. Mukhopadhyay AU - Samudrala Gourinath AU - Sankar Maiti TI - Presence of WH2 like domain in VgrG-1 toxin of <em>Vibrio cholerae</em> reveals the molecular mechanism of actin cross-linking AID - 10.1101/226605 DP - 2017 Jan 01 TA - bioRxiv PG - 226605 4099 - http://biorxiv.org/content/early/2017/11/29/226605.short 4100 - http://biorxiv.org/content/early/2017/11/29/226605.full AB - Type VI secretion systems (T6SS) plays a crucial role in Vibrio cholerae mediated pathogenicity and predation. Tip of T6SS is homologous to gp27/gp5 complex or tail spike of T4 bacteriophage. VgrG-1 of V. cholerae T6SS is unusual among other VgrG because its effector domain is trans-located into the cytosol of eukaryotic cells with an additional actin cross-linking domain (ACD) at its C terminal end. ACD of VgrG-1 (VgrG-1-ACD) causes T6SS dependent host cell cytotoxicity through actin cytoskeleton disruption to prevent bacterial engulfment by macrophages. ACD mediated actin cross-linking promotes survival of the bacteria in the small intestine of humans, along with other virulence factors; establishes successful infection with the onset of diarrhoea in humans. Our studies demonstrated VgrG-1-ACD can bind to actin besides actin cross-linking activity. Computational analysis of ACD revealed the presence of WH2 domain through which it binds actin. Mutations in WH2 domain lead to loss of actin binding in vitro. VgrG-1-ACD having the mutated WH2 domain cannot cross-link actin efficiently in vitro and manifests less actin cytoskeleton disruption when transfected in HeLa cells.Summary statement Actin cross-linking (ACD) domain of VgrG-1 toxin of Type VI secretion in Vibrio cholera has WASP Homology domain 2 (WH2) domain. ACD interact with actin through WH2 domain, WH2 is essential for ACD mediated cross-linking and disruption of actin cytoskeleton in the host cell.