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

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  • Min Liu, Chinese Academy of Sciences
  • ,
  • Cai Yuan, Fuzhou University
  • ,
  • Jan K. Jensen
  • Baoyu Zhao, Chinese Academy of Sciences
  • ,
  • Yunbin Jiang, Chinese Academy of Sciences
  • ,
  • Longguang Jiang, Chinese Academy of Sciences, Fuzhou University
  • ,
  • Mingdong Huang, Chinese Academy of Sciences, Fuzhou University

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,thispossibleregulatorymechanismhasnotyet 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.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind292
Nummer20
Sider (fra-til)8412-8423
Antal sider12
ISSN0021-9258
DOI
StatusUdgivet - 19 maj 2017

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