Implications of the human serine protease HtrA1 in Alzheimer's disease
Zusammenfassung der Projektergebnisse
The HtrA family represents a unique class of oligomeric serine proteases belonging to the core protease set-up in all forms of life. Their defining feature is the combination of a catalytic domain with one or more C-terminal PDZ domains. The ubiquitously expressed human HTRA1 consists of a partial insulin like growth factor binding protein-7 (IGFBP)-7 domain, a serine protease and one C-terminal PDZ domain. Like all other HtrAs, the basic structural unit of HTRA1 is a trimer and the protein can switch reversibly between active and inactive conformations. Our previous work suggested that human HTRA1 might be involved in amyloid precursor protein processing. Recent data revealed that a genetic variance in the HTRA1 promoter correlates with an earlier onset of Alzheimer's disease and an increase in neuritic plaque formation in patients. In addition, HTRA1 was identified as a tau protease cleaving the elements of tau that are involved in tangle formation into small peptides that do not aggregate. Further studies revealed how, as a single factor, HTRA1 is able to degrade amyloid fibrils in an ATP-independent manner. This PDZ-protease solubilises protein fibrils and disintegrates the fibrillar core structure allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. Thereby, aggregate burden in a cellular model of cytoplasmic tau aggregation is reduced. In general, molecular chaperones and conformation specific proteases are key elements of protein quality control pathways that mediate cellular responses against amyloid fibrils that are hallmarks of various neurological disorders. In addition to dedicated chaperones of the heat shock family, several proteases are involved in tau degradation including calpain and the proteasome, although the latter can be overwhelmed or inhibited by tau fibrils. In contrast to these factors, HTRA1 has several unique features including the combination of two functions in one protein, i.e. disintegration and proteolysis, providing a novel mechanism of counteracting protein aggregation in an ATP-independent manner. As HTRA1 dissolves Aβ1-42 aggregates as well, its disintegration activity might have wider implications.
Projektbezogene Publikationen (Auswahl)
- 2011. HtrA proteases: Regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol 12:152-162
Clausen, T, Kaiser, M, Huber, R and M Ehrmann
- 2011. Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. JACS 133:16958-16969
Sinha, S, Lopes, DHJ., Du, C, Pang, E, Shanmugam, A, Lomakin, A, Talbiersky, P, Tennstädt, A, McDaniel, K., Bakshi, R, Kuo, P-Y, Ehrmann, M, Benedek, G, Loo, JA, Klärner, F-G, Schrader, T, Wang, C and G Bitan
- 2011. Substrate induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol 18:386-388
Trübestein, L, Tennstaedt, A, Mönig, T, Krojer, T, Canellas, F, Kaiser, M Clausen, T and M Ehrmann
- 2012. Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates. J Biol Chem 287:20931-20941
Tennstaedt, A, Poepsel, S, Trübestein, L, Hauske, P, Brockmann, A, Schmidt, N, Irle, I., Sacca, B., Niemeyer, CM, Brandt, R., Ksiezak-Reding, H., Tirniceriu, AL, Egensperger, R., Baldi, A., Dehmelt, L, Kaiser, M., Huber, R., Clausen, T and M Ehrmann
(Siehe online unter https://doi.org/10.1074/jbc.M111.316232) - EP2171089 "Screening method for polymorphic markers in HTRA1 gene in neurodegenerate disorders"
Ehrmann, M, Egensperger, R and Tennstaedt, A
