This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We would like to determine the shape of homodimeric, 90-residue alpha- crystallin domains from A;B-Crystallin (A;B) and HSP27 under different conditions of pH. A-crystallin domains are conserved domains in highly oligomeric small Heat Shock Proteins (sHSPs, e.g. A;B and HSP27) that help maintain protein homeostasis as part of the cellular protection system against stress such as changes in temperature or pH. pH-dependent structural changes are observed in the wild type (wt) A-crystallin domain from A;B and not observed in an inherited disease-associated missense mutant, R120G. Our solution state NMR studies show that the structure of the wt and mutant domains are essentially the same at neutral pH. We hypothesize that the shapes of the domains may undergo a pH-dependent change that drives the changes observed in oligomers. We are currently calculating and refining solution-state structures of the A-crystallin domains in anticipation of submitting a manuscript in late spring. Our plan is to include SAXS data collected on samples as a function of pH as an independent measure of pH-induced structural changes.
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