Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor

Charles Bayly-Jones (Leading Author), Christopher J. Lupton (Leading Author), Claudia Fritz (Leading Author), Hariprasad Venugopal, Daniel Ramsbeck, Michael Wermann, Christian Jäger, Alex de Marco, Dagmar Schlenzig (Leading Author), Stephan Schilling, James C. Whisstock (Leading Author)

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin β, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin β reveal unique features of the active site of meprin α, and helical assembly more broadly.

Original languageEnglish
Article number6178
Number of pages14
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

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