5EZD

Crystal structure of a Hepatocyte growth factor activator inhibitor-1 (HAI-1) fragment covering the PKD-like 'internal' domain and Kunitz domain 1

Summary for 5EZD

• Entry DOI: 10.2210/pdb5ezd/pdb
• Descriptor: Kunitz-type protease inhibitor 1, POTASSIUM ION, ACETATE ION, ... (4 entities in total)
• Functional Keywords: transmembrane, multidomain, serine protease inhibitor, tertiary structure, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: O43278
• Total number of polymer chains: 2
• Total formula weight: 33765.88

Authors

Hong, Z.,Andreasen, P.A.,Morth, J.P.,Jensen, J.K. (deposition date: 2015-11-26, release date: 2016-05-18, Last modification date: 2024-10-23)

Primary citation

Hong, Z.,De Meulemeester, L.,Jacobi, A.,Pedersen, J.S.,Morth, J.P.,Andreasen, P.A.,Jensen, J.K.
Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1: FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZ-TYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN.
J.Biol.Chem., 291:14340-14355, 2016

PubMed Abstract: Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain).

PubMed: 27189939
DOI: 10.1074/jbc.M115.707240

Experimental method

X-RAY DIFFRACTION (2.1 Å)