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The L49F mutation in alpha erythroid spectrin induces local disorder in the tetramer association region: Fluorescence and molecular dynamics studies of free and bound alpha spectrin
Author(s) -
Song Yuanli,
Pipalia Nina H.,
Fung L. W.M.
Publication year - 2009
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.202
Subject(s) - tetramer , spectrin , helix (gastropod) , chemistry , molecular dynamics , crystallography , protein structure , helix bundle , alpha helix , biophysics , stereochemistry , circular dichroism , biology , cytoskeleton , biochemistry , ecology , computational chemistry , snail , cell , enzyme
The bundling of the N‐terminal, partial domain helix (Helix C′) of human erythroid α‐spectrin (αI) with the C‐terminal, partial domain helices (Helices A′ and B′) of erythroid β‐spectrin (βI) to give a spectrin pseudo structural domain (triple helical bundle A′B′C′) has long been recognized as a crucial step in forming functional spectrin tetramers in erythrocytes. We have used apparent polarity and Stern–Volmer quenching constants of Helix C′ of αI bound to Helices A′ and B′ of βI, along with previous NMR and EPR results, to propose a model for the triple helical bundle. This model was used as the input structure for molecular dynamics simulations for both wild type (WT) and αI mutant L49F. The simulation output structures show a stable helical bundle for WT, but not for L49F. In WT, four critical interactions were identified: two hydrophobic clusters and two salt bridges. However, in L49F, the region downstream of Helix C′ was unable to assume a helical conformation and one critical hydrophobic cluster was disrupted. Other molecular interactions critical to the WT helical bundle were also weakened in L49F, possibly leading to the lower tetramer levels observed in patients with this mutation‐induced blood disorder.