May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Structural Basis of Chaperone Inhibition by Alfa A-Crystallin Mutant F71G
Author Affiliations & Notes
  • P.N. Farnsworth
    Pharmacology/Physiology & Ophthalmology, UMD-New Jersey Medical School, Newark, NJ, United States
  • P.H. Frederikse
    Pharmacology/Physiology & Ophthalmology, UMD-New Jersey Medical School, Newark, NJ, United States
  • J.E. Kerrigan
    Pharmacology, UMD-Robert Wood Johnson Medical School, Piscataway, NJ, United States
  • Footnotes
    Commercial Relationships  P.N. Farnsworth, None; P.H. Frederikse, None; J.E. Kerrigan, None.
  • Footnotes
    Support  Research to Prevent Blindness
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 2370. doi:
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      P.N. Farnsworth, P.H. Frederikse, J.E. Kerrigan; Structural Basis of Chaperone Inhibition by Alfa A-Crystallin Mutant F71G . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2370.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: The single mutation, F71G, (Sharma et al., 2000) inhibits chaperone activity of αA and its mini-chaperone, K70 to K88. Our goal is to use a molecular dynamics simulation of the wild type αA ß-sheet of D69-H79 and its mutant to investigate the structural basis for this inhibition. Methods: The GROMACS molecular dynamics software package was used to simulate the ß-sheets formed when the wt and mutant sequences are self-aligned in an anti-parallel fashion and to determine the effects of increased temperature on the stability of these ß-sheets. Results: Unlike the linear ß-sheets modeled in vacuo, our simulations of both sequences in a water box produce the most common right-handed twist stabilized by hydrogen bonds, hydrophobic interactions and salt bridges. With increased temperature, which usually accompanies increased chaperone activity; the F71 is essential for unwinding of the ß-sheet resulting in an increased surface area exposure and volume. Increased temperature of the mutant results in a net stabilization of the ß-sheet resulting in a decreased surface area exposure and volume. Conclusion: The D69-H79 sequence of αA has the structural flexibility to modulate subunit-subunit interactions and chaperone activity. Our procedure provides a method for dynamic structural simulations and evaluation of mutations prior to experimentation.

Keywords: chaperones • crystallins • protein structure/function 
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