5h7v

Publication Abstract from PubMed

Hepatocyte growth factor activator inhibitor 1 (HAI-1) is a membrane-bound multi-domain 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 in vivo. The full-length extracellular portion of HAI-1 (sHAI-1) shows weaker inhibitory activity toward target proteases than do the smaller fragments, suggesting auto-inhibition of HAI-1. But this possible regulatory mechanism has not yet been evaluated. Here, we solved the crystal structure of sHAI-1, together with its solution structure determined 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 multi-domain 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's inhibitory activities and might help point to new approaches for better controlling these activities.

The Crystal Structure of a Membrane-bound Multi-domain Protease Inhibitor Reveals the Mechanism of Its Auto-inhibition.,Liu M, Yuan C, Jensen J, Zhao B, Jiang Y, Jiang L, Huang M J Biol Chem. 2017 Mar 27. pii: jbc.M117.779256. doi: 10.1074/jbc.M117.779256. PMID:28348076^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.