The protease GtgE from Salmonella exclusively targets inactive Rab GTPases
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The protease GtgE from Salmonella exclusively targets inactive Rab GTPases. / Wachtel, Rudolf; Bräuning, Bastian; Mader, Sophie L; Ecker, Felix; Kaila, Ville R I; Groll, Michael; Itzen, Aymelt.
In: NAT COMMUN, Vol. 9, No. 1, 01.2018, p. 44.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The protease GtgE from Salmonella exclusively targets inactive Rab GTPases
AU - Wachtel, Rudolf
AU - Bräuning, Bastian
AU - Mader, Sophie L
AU - Ecker, Felix
AU - Kaila, Ville R I
AU - Groll, Michael
AU - Itzen, Aymelt
PY - 2018/1
Y1 - 2018/1
N2 - Salmonella infections require the delivery of bacterial effectors into the host cell that alter the regulation of host defense mechanisms. The secreted cysteine protease GtgE from S. Typhimurium manipulates vesicular trafficking by modifying the Rab32 subfamily via cleaving the regulatory switch I region. Here we present a comprehensive biochemical, structural, and computational characterization of GtgE in complex with Rab32. Interestingly, GtgE solely processes the inactive GDP-bound GTPase. The crystal structure of the Rab32:GDP substrate in complex with the inactive mutant GtgEC45A reveals the molecular basis of substrate recognition. In combination with atomistic molecular dynamics simulations, the structural determinants for protein and activity-state specificity are identified. Mutations in a central interaction hub lead to loss of the strict GDP specificity. Our findings shed light on the sequence of host cell manipulation events during Salmonella infection and provide an explanation for the dependence on the co-secreted GTPase activating protein SopD2.
AB - Salmonella infections require the delivery of bacterial effectors into the host cell that alter the regulation of host defense mechanisms. The secreted cysteine protease GtgE from S. Typhimurium manipulates vesicular trafficking by modifying the Rab32 subfamily via cleaving the regulatory switch I region. Here we present a comprehensive biochemical, structural, and computational characterization of GtgE in complex with Rab32. Interestingly, GtgE solely processes the inactive GDP-bound GTPase. The crystal structure of the Rab32:GDP substrate in complex with the inactive mutant GtgEC45A reveals the molecular basis of substrate recognition. In combination with atomistic molecular dynamics simulations, the structural determinants for protein and activity-state specificity are identified. Mutations in a central interaction hub lead to loss of the strict GDP specificity. Our findings shed light on the sequence of host cell manipulation events during Salmonella infection and provide an explanation for the dependence on the co-secreted GTPase activating protein SopD2.
KW - Bacterial Proteins
KW - Cysteine Proteases
KW - Molecular Dynamics Simulation
KW - Protein Conformation
KW - Salmonella enterica
KW - rab GTP-Binding Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41467-017-02110-1
DO - 10.1038/s41467-017-02110-1
M3 - SCORING: Journal article
C2 - 29298974
VL - 9
SP - 44
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -