De regeling en ontregeling van kleine heat shock eiwitten en een geassocieerd co-chaperone in gezondheid en ziekte
13 december 2019
UAntwerpen, Campus Drie Eiken, Gebouw O, Auditorium O4 - Universiteitsplein 1 - 2610 Wilrijk (Antwerpen) (route: UAntwerpen, Campus Drie Eiken
16 - 18 uur
Vincent Timmerman, Stuart Maudsley
Doctoraatsverdediging Elias Adriaenssens - Departement Biomedische Wetenschappen
Small heat shock proteins are molecular chaperones which prevent misfolded proteins from aggregating. Many aspects regarding the molecular mechanisms of small heat shock proteins, both in health and disease, remain to be unraveled.
In this thesis we found that mammalian small heat shock proteins are targeted to the mitochondrial intermembrane space. While small heat shock proteins of plants are targeted to virtually every membrane-enclosed compartment, this is the first example of mammalian small heat shock proteins to have an organelle-localization. This previously unknown mitochondrial function of HSPB1 is disturbed by CMT disease-causing mutations. One of the most severe HSPB1 mutations is located in a conserved IxI/V motif in the C-terminal domain. This mutation is known to cause the formation of extremely large oligomers, which we found to prevent HSPB1 from being imported into mitochondria.
The underlying structural changes, associated to the formation of these large mutant oligomers, were so far poorly characterized. In this thesis we identified an unexpected mechanism underlying the structural changes. The substitution of Pro182 with Leu allows the IxI/V peptide to sample a larger conformational space and the peptide therefore finds itself less frequently in the required conformation to bind the hydrophobic cleft. As a consequence, other IxI/V containing proteins can bind more to HSPB1, explaining the altered protein-protein interactions.
Finally, the co-chaperone BAG3 forms a protein scaffold which binds both small heat proteins and Hsp70. As such, it brings both arms of protein surveillance together. In this thesis we studied three different mutations in the IPV-motif of BAG3, which is where small heat shock proteins bind BAG3, and found that they induce aggresome formation. As a result of that, mutant BAG3 traps the small heat shock proteins and Hsp70 at the aggresome which leads to a general collapse in the chaperone-network.