Journal Article

PUBDB-2021-04851

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

Pihl, R. ; Jensen, R. K. ; Poulsen, E. C. ; Jensen, L. ; Hansen, A. G. ; Thøgersen, I. B. ; Dobó, J. ; Gál, P. ; Andersen, G. R. ; Enghild, J. J. ; Thiel, S. (Corresponding author)

2021
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.aba7381  doi:10.3204/PUBDB-2021-04851

Abstract: 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2021

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