Legionella effector MavC targets the Ube2N~Ub conjugate for noncanonical ubiquitination

Kedar Puvar, Shalini Iyer, Jiaqi Fu, Sebastian Kenny, Kristos I. Negrón Terón, Zhao-Qing Luo, Peter S. Brzovic, Rachel E. Klevit () and Chittaranjan Das ()
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Kedar Puvar: Purdue University
Shalini Iyer: Purdue University
Jiaqi Fu: Purdue University
Sebastian Kenny: Purdue University
Kristos I. Negrón Terón: Purdue University
Zhao-Qing Luo: Purdue University
Peter S. Brzovic: University of Washington
Rachel E. Klevit: University of Washington
Chittaranjan Das: Purdue University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The bacterial effector MavC modulates the host immune response by blocking Ube2N activity employing an E1-independent ubiquitin ligation, catalyzing formation of a γ-glutamyl-ε-Lys (Gln40Ub-Lys92Ube2N) isopeptide crosslink using a transglutaminase mechanism. Here we provide biochemical evidence in support of MavC targeting the activated, thioester-linked Ube2N~ubiquitin conjugate, catalyzing an intramolecular transglutamination reaction, covalently crosslinking the Ube2N and Ub subunits effectively inactivating the E2~Ub conjugate. Ubiquitin exhibits weak binding to MavC alone, but shows an increase in affinity when tethered to Ube2N in a disulfide-linked substrate that mimics the charged E2~Ub conjugate. Crystal structures of MavC in complex with the substrate mimic and crosslinked product provide insights into the reaction mechanism and underlying protein dynamics that favor transamidation over deamidation, while revealing a crucial role for the structurally unique insertion domain in substrate recognition. This work provides a structural basis of ubiquitination by transglutamination and identifies this enzyme’s true physiological substrate.

Date: 2020
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DOI: 10.1038/s41467-020-16211-x

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