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The relationship between conservation, thermodynamic stability, and function in the SH3 domain hydrophobic core.

Abstract：

:To investigate the relationships between sequence conservation, protein stability, and protein function, we have measured the thermodynamic stability, folding kinetics, and in vitro peptide-binding activity of a large number of single-site substitutions in the hydrophobic core of the Fyn SH3 domain. Comparison of these data to that derived from an analysis of a large alignment of SH3 domain sequences revealed a very good correlation between the distinct pattern of conservation observed at each core position and the thermodynamic stability of mutants. Conservation was also found to correlate well with the unfolding rates of mutants, but not to the folding rates, suggesting that evolution selects more strongly for optimal native state packing interactions than for maximal folding rates. Structural analysis suggests that residue-residue core packing interactions are very similar in all SH3 domains, which provides an explanation for the correlation between conservation and mutant stability effects studied in a single SH3 domain. We also demonstrate a correlation between stability and the in vivo activity of mutants, and between conservation and activity. However, the relationship between conservation and activity was very strong only for the three most conserved hydrophobic core positions. The weaker correlation between activity and conservation seen at the other seven core positions indicates that maintenance of protein stability is the dominant selective pressure at these positions. In general, the pattern of conservation at hydrophobic core positions appears to arise from conserved packing constraints, and can be effectively utilized to predict the destabilizing effects of amino acid substitutions.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Di Nardo AA,Larson SM,Davidson AR

doi

10.1016/j.jmb.2003.08.035

keywords:

subject

Has Abstract

pub_date

2003-10-24 00:00:00

pages

641-55

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022283603010313

journal_volume

333

pub_type

杂志文章

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