Differential domain structure stability of the severe acute respiratory syndrome coronavirus papain-like protease

► A reversible three-state unfolding of PLpro was identified. ► The zinc-binding domain starts to unfold during the first transition. ► Eighty percentage of activity loss at the first transition indicated the importance of zinc domain. ► PLpro displayed differential domain structure stability. ► The present studies help to understand the fold of other DUBs with similar scaffold.