Smaller oligomeric chaperones of α-crystallins (αA- and αB-) have received increasing
attention due to their improved therapeutic potential in preventing protein aggregating diseases.
Our previous study suggested that deleting 54–61 residues from the N-terminal domain (NTD) of
αB-crystallin (αB∆54–61) decreases the oligomer size and increases the chaperone function. Several studies have also suggested that NTD plays a significant role in protein oligomerization and
chaperone function. The current study was undertaken to assess the effect of deleting conserved
21–28 residues from the activated αB∆54–61 (to get αB∆21–28, ∆54–61) on the structure–function of
recombinant αB∆21... More
Smaller oligomeric chaperones of α-crystallins (αA- and αB-) have received increasing
attention due to their improved therapeutic potential in preventing protein aggregating diseases.
Our previous study suggested that deleting 54–61 residues from the N-terminal domain (NTD) of
αB-crystallin (αB∆54–61) decreases the oligomer size and increases the chaperone function. Several studies have also suggested that NTD plays a significant role in protein oligomerization and
chaperone function. The current study was undertaken to assess the effect of deleting conserved
21–28 residues from the activated αB∆54–61 (to get αB∆21–28, ∆54–61) on the structure–function of
recombinant αB∆21–28, ∆54–61. The αB∆21–28, ∆54–61 mutant shows an 80% reduction in oligomer
size and 3- to 25-fold increases in chaperone activity against model substrates when compared to
αB-WT. Additionally, the αB∆21–28, ∆54–61 was found to prevent β-amyloid (Aβ1–42) fibril formation in vitro and suppressed Aβ1–42-induced cytotoxicity in ARPE-19 cells in a more effective manner
than seen with αB-WT or αB∆54–61. Cytotoxicity and reactive oxygen species (ROS) detection
studies with sodium iodate (SI) showed that the double mutant protein has higher anti-apoptotic
and anti-oxidative activities than the wild-type or αB∆54–61 in oxidatively stressed cells. Our study
shows that the residues 21–28 and 54–61 in αB-crystallin contribute to the oligomerization and modulate chaperone function. The deletion of conserved 21–28 residues further potentiates the activated
αB∆54–61. We propose that increased substrate affinity, altered subunit structure, and assembly
leading to smaller oligomers could be the causative factors for the increased chaperone activity of
αB∆21–28, ∆54–61
