The molecular architecture of alphaB-crystallin reveals insights into its chaperone function and activation

The molecular chaperone αB-crystallin protects eye lens proteins from stress-induced aggregation. In non-lenticular cells, it is involved in various neurodegenerative diseases, multiple sclerosis and cancer. Its cellular function is to bind to partially unfolded polypeptides and maintain them in a refolding-competent state. This holdase function allows to separate the binding of unfolded polypeptides from the refolding by ATP-dependent chaperones. Thereby, αB-crystallin sustains proteostasis. We constructed a pseudo-atomic model of a 24meric αB-crystallin assembly obtained by a hybrid approach combining cryo-electron microscopy and molecular modeling. Furthermore, we analysed the molecular architectures of additional oligomeric assemblies of αB-crystallin with different quaternary structures. This hetero-geneity is achieved by a small set of defined structural variations that modulate the oligomer equilibrium of αB-crystallin and thus, its chaperone activity. Based on these structural data, we were able to elucidate how αB-crystallin interacts with physiologically relevant substrate proteins in more detail and to understand its activation by phosphorylation.