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  • Nonnative interactions regulate folding and switching of myristoylated protein.

Nonnative interactions regulate folding and switching of myristoylated protein.

Proceedings of the National Academy of Sciences of the United States of America (2012-08-01)
Dalit Shental-Bechor, Martin T J Smith, Duncan Mackenzie, Aron Broom, Amir Marcovitz, Fadila Ghashut, Chris Go, Fernando Bralha, Elizabeth M Meiering, Yaakov Levy
ABSTRACT

We present an integrated experimental and computational study of the molecular mechanisms by which myristoylation affects protein folding and function, which has been little characterized to date. Myristoylation, the covalent linkage of a hydrophobic C14 fatty acyl chain to the N-terminal glycine in a protein, is a common modification that plays a critical role in vital regulated cellular processes by undergoing reversible energetic and conformational switching. Coarse-grained folding simulations for the model pH-dependent actin- and membrane-binding protein hisactophilin reveal that nonnative hydrophobic interactions of the myristoyl with the protein as well as nonnative electrostatic interactions have a pronounced effect on folding rates and thermodynamic stability. Folding measurements for hydrophobic residue mutations of hisactophilin and atomistic simulations indicate that the nonnative interactions of the myristoyl group in the folding transition state are nonspecific and robust, and so smooth the energy landscape for folding. In contrast, myristoyl interactions in the native state are highly specific and tuned for sensitive control of switching functionality. Simulations and amide hydrogen exchange measurements provide evidence for increases as well as decreases in stability localized on one side of the myristoyl binding pocket in the protein, implicating strain and altered dynamics in switching. The effects of folding and function arising from myristoylation are profoundly different from the effects of other post-translational modifications.

MATERIALS
Product Number
Brand
Product Description

Supelco
Myristic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Myristic acid, ≥98.0% (GC)
Supelco
Myristic acid, analytical standard
Sigma-Aldrich
Myristic acid, ≥95%, FCC, FG
Sigma-Aldrich
Myristic acid, natural, ≥98.5%, FG
Sigma-Aldrich
Myristic acid, Sigma Grade, ≥99%