Abstract:
:The naturally occurring amino acid cysteine has often been implicated with a crucial role in maintaining protein structure and stability. An intriguing duality in the intrinsic hydrophobicity of the cysteine side chain is that it exhibits both polar as well as hydrophobic characteristics. Here, we have utilized a cysteine-scanning mutational strategy on the transmembrane β-barrel PagP to examine the membrane depth-dependent energetic contribution of the free cysteine side chain (thiolate) versus the parent residue at an experimental pH of 9.5 in phosphatidylcholine vesicles. We find that introduction of cysteine causes destabilization at several of the 26 lipid-facing sites of PagP that we mutated in this study. The destabilization is minimal (0.5-1.5 kcal/mol) when the mutation is toward the bilayer midplane, whereas it is higher in magnitude (3.0-5.0 kcal/mol) near the bilayer interface. These observations suggest that cysteine forms more favorable interactions with the hydrophobic lipid core as compared to the amphiphilic water-lipid interface. The destabilizing effect is more pronounced when cysteine replaces the interfacial aromatics, which are known to participate in tertiary interaction networks in transmembrane β-barrels. Our observations from experiments involving the introduction of cysteine at the bilayer midplane further strengthen previous views that the free cysteine side chain does possess strongly apolar characteristics. Additionally, the free energy changes observed upon cysteine incorporation show a depth-dependent correlation with the estimated energetic cost of partitioning derived from reported hydrophobicity scales. Our results and observations from the thermodynamic analysis of the PagP barrel may explain why cysteine, despite possessing a polar sulfhydryl group, tends to behave as a hydrophobic (rather than polar) residue in folded protein structures.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Iyer BR,Mahalakshmi Rdoi
10.1016/j.bpj.2019.05.024subject
Has Abstractpub_date
2019-07-09 00:00:00pages
25-35issue
1eissn
0006-3495issn
1542-0086pii
S0006-3495(19)30444-8journal_volume
117pub_type
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