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Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket

Pruthvi Raj Bejugam1, Raja R Kuppili, Nitu Singh

  • 1Advanced Centre for Treatment, Research and Education in Cancer ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India.

Plos One
|March 5, 2013
PubMed

Insights

HtrA2 (High temperature requirement A2) protease activity is regulated by a novel allosteric mechanism. A unique binding pocket initiates signals to the active site, offering new therapeutic strategies for cancer and neurodegenerative diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • HtrA2 (High temperature requirement A2) is a proapoptotic serine protease implicated in cancer and neurodegenerative diseases.
  • Its C-terminal PDZ domain regulates function via conformational changes, but the mechanism remains unclear.
  • Allosteric regulation has been observed in HtrA2 homologs but not yet characterized in HtrA2 itself.

Purpose of the Study:

  • To investigate the presence and mechanism of allosteric regulation in HtrA2.
  • To identify novel regulatory sites and understand their role in HtrA2 function.
  • To explore HtrA2 as a therapeutic target by elucidating its regulatory mechanisms.

Main Methods:

  • In silico computational modeling.
  • Biochemical assays to validate computational findings.
  • Structural analysis of HtrA2 and its interactions.

Main Results:

  • Demonstrated that allostery significantly regulates HtrA2 activity.
  • Identified a novel, non-canonical selective binding pocket in HtrA2.
  • Characterized a complex allosteric mechanism initiating signal propagation to the active site.

Conclusions:

  • HtrA2 activity is controlled by a unique allosteric mechanism involving a non-classical binding pocket.
  • This discovery reveals a novel regulatory pathway for HtrA2, distinct from other HtrA family members.
  • Understanding this mechanism opens new avenues for therapeutic interventions targeting HtrA2 in diseases like cancer and neurodegeneration.

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