title: Nonnative interactions regulate folding and switching of myristoylated protein.
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.
authors: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Dalit
authors: D
authors: Shental-Bechor
authors: Martin T J
authors: MT
authors: Smith
authors: Duncan
authors: D
authors: Mackenzie
authors: Aron
authors: A
authors: Broom
authors: Amir
authors: A
authors: Marcovitz
authors: Fadila
authors: F
authors: Ghashut
authors: Chris
authors: C
authors: Go
authors: Fernando
authors: F
authors: Bralha
authors: Elizabeth M
authors: EM
authors: Meiering
authors: Yaakov
authors: Y
authors: Levy
mesh_terms: D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D019814:Myristic Acid / Q000737:chemistry*; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D011506:Proteins; D019814:Myristic Acid