An allosteric HTRA1-calpain 2 complex with restricted activation profile

Zymogen activation is a widely conserved regulatory principle across protease clans. It describes the irreversible activation by processing of the inactive zymogen precursor by an active protease. Here we report an alternative and reversible mechanism of protease activation, where the activator is an inactive protease. This mechanism involves the formation of an allosteric complex between the serine PDZ protease HTRA1 and the cysteine protease calpain 2. Surprisingly, the allosteric activation of HTRA1 is restricted to a subset of substrate conformations as it improves the proteolysis of soluble tau protein but not the dissociation and degradation of amyloid fibrils that are a prominent hallmark of Alzheimer's disease. These data exemplify an additional challenge for protein quality control factors such as HTRA1 in the clearing of pathogenic fibrils and suggest a potential for unexpected side effects of chemical modulators targeting allosteric sites.