title: Destabilizing mutations promote membrane protein misfolding.
abstract: In this work, the relationship between stability and propensity to misfold was probed for a series of purified variants of the polytopic integral membrane protein diacylglycerol kinase. It was observed that there was a strong correlation between stability and folding efficiency. The most common mutations that promoted misfolding were those which also destabilized the protein. These results imply that by targeting unstable membrane proteins for degradation, cellular protein folding quality control can eliminate proteins that have a high intrinsic propensity to misfold into aberrant structures. Moreover, the more rare class of amino acid mutations that promote misfolding without perturbing stability may be particularly dangerous because the mutant proteins may evade the surveillance of cellular quality control systems.
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, USA.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Nagy
authors.forename: Charles R
authors.initials: CR
authors.lastname: Sanders
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D019852:Diacylglycerol Kinase / Q000737:chemistry* / Q000235:genetics*; D004795:Enzyme Stability / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics; D014644:Genetic Variation; D019791:Guanidine / Q000737:chemistry; D007700:Kinetics; D008081:Liposomes; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008823:Micelles; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010713:Phosphatidylcholines / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D008081:Liposomes; D008565:Membrane Proteins; D008823:Micelles; D010713:Phosphatidylcholines; D019852:Diacylglycerol Kinase; D019791:Guanidine; D003545:Cysteine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine