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Published on: May 24, 2024
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An allosteric HTRA1-calpain 2 complex with restricted activation profile
Juliana Rey1, Maike Breiden1, Vanda Lux1
1Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitaetsstrasse, 45141 Essen, Germany.
Summary
A novel reversible activation mechanism for proteases involves a complex of HTRA1 and calpain 2. This interaction enhances soluble tau proteolysis but hinders amyloid fibril degradation, posing challenges for protein quality control.
Area of Science:
- Biochemistry
- Molecular Biology
- Protease Function
Background:
- Classic serine proteases activate irreversibly through proteolytic processing of inactive precursors.
- Protein aggregation, such as tau amyloid fibrils, presents challenges for cellular clearance mechanisms.
Purpose of the Study:
- To investigate an alternative, reversible protease activation mechanism.
- To explore the role of the HTRA1 and calpain 2 complex in tau protein and fibril processing.
Main Methods:
- Biochemical assays to study protease activity.
- Analysis of protein complex formation between HTRA1 and calpain 2.
- Investigating the proteolysis of soluble tau and tau amyloid fibrils.
Main Results:
- A reversible activation mechanism involving an inactive protease (calpain 2) and HTRA1 was identified.
- The HTRA1-calpain 2 complex selectively enhanced soluble tau proteolysis.
- The complex failed to efficiently degrade tau amyloid fibrils, unlike free HTRA1.
Conclusions:
- This study reveals a unique reversible protease activation pathway with implications for protein quality control.
- The findings highlight challenges in clearing pathogenic protein aggregates and potential off-target effects of protease modulators.
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