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Merck

ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism.

Science advances (2021-02-02)
Rasmus Pihl, Rasmus K Jensen, Emil C Poulsen, Lisbeth Jensen, Annette G Hansen, Ida B Thøgersen, József Dobó, Péter Gál, Gregers R Andersen, Jan J Enghild, Steffen Thiel
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ITIH4 antibody produced in rabbit, Ab1, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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1 g
1 Estimated to ship on February 23, 2025
MXP 947.00
5 g
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MXP 2,440.00
25 g
1 Estimated to ship on February 23, 2025
MXP 5,865.00

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Sigma-Aldrich
Kallikrein from human plasma, buffered aqueous solution, ≥5 units/mg protein
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1 g
1 Estimated to ship on February 23, 2025
MXP 947.00
5 g
1 Estimated to ship on February 23, 2025
MXP 2,440.00
25 g
1 Estimated to ship on February 23, 2025
MXP 5,865.00

To order products, please contact your local dealer.

Sigma-Aldrich
Kininogen, High Molecular Weight, Single Chain, Human Plasma, Native, single chain, high molecular weight Kininogen from human plasma.
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SKUPack SizeAvailabilityPrice
1 g
1 Estimated to ship on February 23, 2025
MXP 947.00
5 g
1 Estimated to ship on February 23, 2025
MXP 2,440.00
25 g
1 Estimated to ship on February 23, 2025
MXP 5,865.00

To order products, please contact your local dealer.