Structural and Mechanistic Implications of Metal-Binding in the Small Heat-Shock Protein αB-Crystallin

摘要: The human small heat-shock protein αB-crystallin (αB) rescues misfolded proteins from irreversible aggregation during cellular stress. Binding of Cu(II) was shown to modulate the oligomeric architecture and chaperone activity αB. However, mechanistic basis this stimulation is so far not understood. We provide here first structural insights into Cu(II)-mediated modulation function using NMR spectroscopy other biophysical approaches. show that α-crystallin domain elementary Cu(II)-binding unit specifically coordinating one ion with picomolar binding affinity. Putative ligands are His83, His104, His111, Asp109 at dimer interface. These loop residues conserved among different metazoans, but also for αA-crystallin, HSP20, HSP27. involvement has direct implications stability, because residue forms a salt bridge disease-related Arg120 neighboring monomer. Furthermore, we observe reorganization strands β2-β3 triggered by binding. This N-terminal region known mediate both intermolecular arrangement in αB oligomers client proteins. In presence Cu(II), size heterogeneity multimers increased. At same time, increases toward lens-specific βL-crystallin. therefore suggest unblocks potential sites alters quaternary dynamics dimeric building block as well higher order assemblies