Figure 7.

Model summarizing the catalytic mechanism of K48-linked polyUb

(A) MINDY1 and MINDY2 exist in an autoinhibited conformation in which the Cys loop is in a closed conformation that sterically interferes with Ub binding and also contributes to keeping the catalytic site inhibited.

(B) In a substrate-driven mechanism, Ub interactions release inhibition and activate the DUB, resulting in chain cleavage and release of the Ub chain.

(C) In the product intermediate transitional tetrahedral state, the Ub occupies the S1 site. As this is not a strong binding interface, this Ub exists in 2 different conformers.

Attack by a water molecule releases the Ub and returns the DUB to an inhibited conformation. Created using Illustrate (Goodsell et al., 2019).

See also Figure S8.