Ten catalytic snapshots of rhomboid intramembrane proteolysis from gate opening to peptide release.

ABSTRACT: Protein cleavage inside the cell membrane triggers various pathophysiological signaling pathways, but the mechanism of catalysis is poorly understood. We solved ten structures of the Escherichia coli rhomboid protease in a bicelle membrane undergoing time-resolved steps that encompass the entire proteolytic reaction on a transmembrane substrate and an aldehyde inhibitor. Extensive gate opening accompanied substrate, but not inhibitor, binding, revealing that substrates and inhibitors take different paths to the active site. Catalysis unexpectedly commenced with, and was guided through subsequent catalytic steps by, motions of an extracellular loop, with local contributions from active site residues. We even captured the elusive tetrahedral intermediate that is uncleaved but covalently atta

SUBMITTER: Cho S 

PROVIDER: S-EPMC6858540 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature