title: Folding of proteins with a flavodoxin-like architecture.
abstract: The flavodoxin-like fold is a protein architecture that can be traced back to the universal ancestor of the three kingdoms of life. Many proteins share this α-β parallel topology and hence it is highly relevant to illuminate how they fold. Here, we review experiments and simulations concerning the folding of flavodoxins and CheY-like proteins, which share the flavodoxin-like fold. These polypeptides tend to temporarily misfold during unassisted folding to their functionally active forms. This susceptibility to frustration is caused by the more rapid formation of an α-helix compared to a β-sheet, particularly when a parallel β-sheet is involved. As a result, flavodoxin-like proteins form intermediates that are off-pathway to native protein and several of these species are molten globules (MGs). Experiments suggest that the off-pathway species are of helical nature and that flavodoxin-like proteins have a nonconserved transition state that determines the rate of productive folding. Folding of flavodoxin from Azotobacter vinelandii has been investigated extensively, enabling a schematic construction of its folding energy landscape. It is the only flavodoxin-like protein of which cotranslational folding has been probed. New insights that emphasize differences between in vivo and in vitro folding energy landscapes are emerging: the ribosome modulates MG formation in nascent apoflavodoxin and forces this polypeptide toward the native state.
authors.affiliation: Laboratory of Biochemistry, Wageningen University and Research, The Netherlands.
authors.forename: Joseline A
authors.initials: JA
authors.lastname: Houwman
authors.affiliation: Laboratory of Biochemistry, Wageningen University and Research, The Netherlands.
authors.forename: Carlo P M
authors.initials: CPM
authors.lastname: van Mierlo
mesh_terms: D016948:Azotobacter vinelandii / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins; D005418:Flavodoxin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D000072236:Methyl-Accepting Chemotaxis Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D014176:Protein Biosynthesis; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D005418:Flavodoxin; D000072236:Methyl-Accepting Chemotaxis Proteins; D020033:Protein Isoforms; C000607606:cheY protein, E coli
keywords: CheY; NtrC; Spo0F; apoflavodoxin; cotranslational folding; frustration; molten globule; off-pathway intermediate; ribosome-nascent chain complex; simulation