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The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition.


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 in vivo 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.

SUBMITTER: Liu M 

PROVIDER: S-EPMC5437246 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition.

Liu Min M   Yuan Cai C   Jensen Jan K JK   Zhao Baoyu B   Jiang Yunbin Y   Jiang Longguang L   Huang Mingdong M  

The Journal of biological chemistry 20170327 20


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 <i>in vivo</i> The full-length extracellular portion of HAI-1 (sHAI-1) shows weaker inhibitory activity toward target protea  ...[more]

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