An allosteric HTRA1-calpain 2 complex with restricted activation profile

Juliana Rey (1) , Maike Breiden (1) , Vanda Lux (1) , Anika Bluemke (1) , Maike Steindel (1) , Kamilla Ripkens (1) , Bastian Möllers (1) , Kenny Bravo Rodriguez (1) , Prisca Boisguerin (2, 3) , Rudolf Volkmer , Joel Mieres-Perez (1) , Tim Clausen (4) , Elsa Sanchez-Garcia (1) , Michael Ehrmann (1, 5)

1 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
2 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
3 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
4 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
5 Cardiff University

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.

Mots clés: HTRA1; Serine protease; Allostery; Amyloid fibrils; Tau

Domaines: Biochimie, Biologie Moléculaire

Juliana Rey, Maike Breiden, Vanda Lux, Anika Bluemke, Maike Steindel, et al.. An allosteric HTRA1-calpain 2 complex with restricted activation profile. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (14), pp.e2113520119. ⟨10.1073/pnas.2113520119⟩. ⟨hal-03625904⟩