Open AccessAn allosteric HTRA1-calpain 2 complex with restricted activation profile
Author(s) -
Juliana Rey,
Maike Breiden,
Vanda Lux,
Anika Bluemke,
Maike Steindel,
Kamilla Ripkens,
Bastian Möllers,
Kenny Bravo Rodriguez,
Prisca Boisguérin,
Rudolf Volkmer,
Joel MieresPerez,
Tim Clausen,
Elsa Sánchez-García,
Michael Ehrmann
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2113520119
Subject(s) - proteases , allosteric regulation , proteolysis , calpain , protease , serine , chemistry , pdz domain , serine protease , biochemistry , enzyme activator , cysteine , microbiology and biotechnology , biophysics , enzyme , biology
Significance Classic serine proteases are synthesized as inactive precursors that are proteolytically processed, resulting in irreversible activation. We report an alternative and reversible mechanism of activation that is executed by an inactive protease. This mechanism involves a protein complex between the serine protease HTRA1 and the cysteine protease calpain 2. Surprisingly, activation is restricted as it improves the proteolysis of soluble tau protein but not the dissociation and degradation of its amyloid fibrils, a task that free HTRA1 is efficiently performing. These data exemplify a challenge for protein quality control proteases in the clearing of pathogenic fibrils and suggest a potential for unexpected side effects of chemical modulators targeting PDZ or other domains located at a distance to the active site.