NDLI: Clustering of Large Hydrophobes in the Hydrophobic Core of Two-stranded α-Helical Coiled-Coils Controls Protein Folding and Stability

Content Provider	Journal of Biological Chemistry (JBC)
Author	Kwok, Stanley C. Hodges, Robert S.
Abstract	The de novo design and biophysical characterization of two 60-residue peptides that dimerize to fold as parallel coiled-coils with different hydrophobic core clustering is described. Our goal was to investigate whether designing coiled-coils with identical hydrophobicity but with different hydrophobic clustering of non-polar core residues (each contained 6 Leu, 3 Ile, and 7 Ala residues in the hydrophobic core) would affect helical content and protein stability. The disulfide-bridged P3 and P2 differed dramatically in α-helical structure in benign conditions. P3 with three hydrophobic clusters was 98% α-helical, whereas P2 was only 65% α-helical. The stability profiles of these two analogs were compared, and the enthalpy and heat capacity changes upon denaturation were determined by measuring the temperature dependence by circular dichroism spectroscopy and confirmed by differential scanning calorimetry. The results showed that P3 assembled into a stable α-helical two-stranded coiled-coil and exhibited a native protein-like cooperative two-state transition in thermal melting, chemical denaturation, and calorimetry experiments. Although both peptides have identical inherent hydrophobicity (the hydrophobic burial of identical non-polar residues in equivalent heptad coiled-coil positions), we found that the context dependence of an additional hydrophobic cluster dramatically increased stability of P3 (ΔTm ≈ 18 °C and Δ[urea]½ ≈ 1.5 m) as compared with P2. These results suggested that hydrophobic clustering significantly stabilized the coiled-coil structure and may explain how long fibrous proteins like tropomyosin maintain chain integrity while accommodating polar or charged residues in regions of the protein hydrophobic core.
Related Links	http://www.jbc.org/content/278/37/35248.abstract
Ending Page	35254
Starting Page	35248
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	37
Volume Number	278
DOI	10.1074/jbc.M305306200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2003-09-12
Access Restriction	Open
Subject Keyword	Protein Structure and Folding
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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