; VIB SWITCH Laboratory, KU Leuven
Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly.
Using both Ab and tau as a model system we demonstrate that proteins with local sequence homology can modify fibril nucleation, morphology and spreading of aggregates in cultured cells2,3. Depending on the type of mutation such interactions inhibit or promote aggregation in a manner that can be predicted from structure. We find that these heterotypic amyloid interactions can result in the subcellular mislocalisation of these proteins. Moreover, equilibrium studies indicate that the critical concentration of aggregation is altered by heterotypic interactions.
Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and we discuss how such sequence specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.
Frederic Rousseau is a Belgian structural biologist and biophysicist affiliated with the Flanders Institute for Biotechnology (VIB) and the University of Leuven (KUL). His scientific research is performed in close collaboration with Joost Schymkowitz, with whom he directs the VIB Switch laboratory since 2003. Frederic and Joost have been a scientific duo since 1998; they obtained their PhDs from the University of Cambridge, UK and completed post-doctoral research at EMBL, Heidelberg. The research of the Switch Lab integrates computational modeling, biophysics, cell biology, chemical biology with in vivo experiments and analysis of patient tissues to investigate the mechanisms of protein misfolding and aggregation. Frederic and Joost are also scientific founders of-, and scientific advisors to Aelin Therapuetics, fa privately held Belgian biotherapeutics company that develops the therapeutic applications of the Pept-inTM technology, invented in the Switch Lab. Frederic and Joost have authored more than 170 peer-reviewed publication in high impact journals, including Nature, Cell and Science, and are inventors on more than 15 patents.
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