5H7V

Structure of full-length extracellular domain of HAI-1 at pH 4.6

Summary for 5H7V

• Entry DOI: 10.2210/pdb5h7v/pdb
• Descriptor: Kunitz-type protease inhibitor 1 (1 entity in total)
• Functional Keywords: hai-1, hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: O43278
• Total number of polymer chains: 1
• Total formula weight: 47295.85

Authors

Liu, M.,Huang, M. (deposition date: 2016-11-21, release date: 2017-03-29, Last modification date: 2024-10-23)

Primary citation

Liu, M.,Yuan, C.,Jensen, J.K.,Zhao, B.,Jiang, Y.,Jiang, L.,Huang, M.
The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition
J. Biol. Chem., 292:8412-8423, 2017

PubMed Abstract: Hepatocyte growth factor activator inhibitor 1 (HAI-1) is a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development and is also important in maintaining postnatal homeostasis in many tissues. HAI-1 is a Kunitz-type serine protease inhibitor, and soluble fragments of HAI-1 with variable lengths have been identified The full-length extracellular portion of HAI-1 (sHAI-1) shows weaker inhibitory activity toward target proteases than the smaller fragments, suggesting auto-inhibition of HAI-1. However, this possible regulatory mechanism has not yet been evaluated. Here, we solved the crystal structure of sHAI-1 and determined the solution structure by small-angle X-ray scattering. These structural analyses revealed that, despite the presence of long linkers, sHAI-1 exists in a compact conformation in which sHAI-1 active sites in Kunitz domain 1 are sterically blocked by neighboring structural elements. We also found that in the presence of target proteases, sHAI-1 adopts an extended conformation that disables the auto-inhibition effect. Our results also reveal the roles of non-inhibitory domains of this multidomain protein and explain the low activity of the full-length protein. The structural insights gained here improve our understanding of the regulation of HAI-1 inhibitory activities and point to new approaches for better controlling these activities.

PubMed: 28348076
DOI: 10.1074/jbc.M117.779256

Experimental method

X-RAY DIFFRACTION (3.82 Å)