Aarhus University Seal / Aarhus Universitets segl

ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

Inter-α-inhibitor heavy chain 4 (ITIH4) is a poorly characterized plasma protein that is proteolytically processed in multiple pathological conditions. However, no biological function of ITIH4 has been identified. Here, we show that ITIH4 is cleaved by several human proteases within a protease-susceptible region, enabling ITIH4 to function as a protease inhibitor. This is exemplified by its inhibition of mannan-binding lectin-associated serine protease-1 (MASP-1), MASP-2, and plasma kallikrein, which are key proteases for intravascular host defense. Mechanistically, ITIH4 acts as bait that, upon cleavage, forms a noncovalent, inhibitory complex with the executing protease that depends on the ITIH4 von Willebrand factor A domain. ITIH4 inhibits the MASPs by sterically preventing larger protein substrates from accessing their active sites, which remain accessible and fully functional toward small substrates. Thus, we demonstrate that ITIH4 functions as a protease inhibitor by a previously undescribed inhibitory mechanism.

OriginalsprogEngelsk
Artikelnummer7381
TidsskriftScience Advances
Vol/bind7
Nummer2
Antal sider17
ISSN2375-2548
DOI
StatusUdgivet - jan. 2021

Bibliografisk note

Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Se relationer på Aarhus Universitet Citationsformater

ID: 209671590