Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding.

Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Research Abstract Details 

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Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Abstract Text:

Shannon L Flaugh,Ishara A Mills,Jonathan King,

Human eye lens transparency requires life long stability and solubility of the crystallin proteins. Aged crystallins have high levels of covalent damage, including glutamine deamidation. Human gammaD-crystallin (HgammaD-Crys) is a two-domain beta-sheet protein of the lens nucleus. The two domains interact through interdomain side chain contacts, including Gln-54 and Gln-143, which are critical for stability and folding of the N-terminal domain of HgammaD-Crys. To test the effects of interface deamidation on stability and folding, single and double glutamine to glutamate substitutions were constructed. Equilibrium unfolding/refolding experiments of the proteins were performed in guanidine hydrochloride at pH 7.0, 37 degrees C, or urea at pH 3.0, 20 degrees C. Compared with wild type, the deamidation mutants were destabilized at pH 7.0. The proteins populated a partially unfolded intermediate that likely had a structured C-terminal domain and unstructured N-terminal domain. However, at pH 3.0, equilibrium unfolding transitions of wild type and the deamidation mutants were indistinguishable. In contrast, the double alanine mutant Q54A/Q143A was destabilized at both pH 7.0 and 3.0. Thermal stabilities of the deamidation mutants were also reduced at pH 7.0. Similarly, the deamidation mutants lowered the kinetic barrier to unfolding of the N-terminal domain. These data indicate that interface deamidation decreases the thermodynamic stability of HgammaD-Crys and lowers the kinetic barrier to unfolding due to introduction of a negative charge into the domain interface. Such effects may be significant for cataract formation by inducing protein aggregation or insolubility.

Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Publishing Authors By Initials

SL Flaugh,IA Mills,J King,

For similar proteins: eye proteins: crystallins: gamma-crystallins research abstracts see: proteins: eye proteins: crystallins: gamma-crystallins research

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Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 281

Page Numbers: 30782-93

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 4

MONTH: 08

YEAR: 2006

Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Keywords Mesh Terms:

KEYWORDS: gamma-Crystallins

MESH TERMS: chemistry

Chemical & Substance for Abstract: Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding. Information

Substance Name: Glutamine

Registry Number: 56-85-9

Grant and Affiliation Information for Glutamine deamidation destabilizes human gammaD-crystallin and lowers the kinetic barrier to unfolding.

AFFILIATION: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM17980

ACRONYM: GM

MEDLINETA: J Biol Chem

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