title: Accurate prediction of cellular co-translational folding indicates proteins can switch from post- to co-translational folding.
abstract: The rates at which domains fold and codons are translated are important factors in determining whether a nascent protein will co-translationally fold and function or misfold and malfunction. Here we develop a chemical kinetic model that calculates a protein domain's co-translational folding curve during synthesis using only the domain's bulk folding and unfolding rates and codon translation rates. We show that this model accurately predicts the course of co-translational folding measured in vivo for four different protein molecules. We then make predictions for a number of different proteins in yeast and find that synonymous codon substitutions, which change translation-elongation rates, can switch some protein domains from folding post-translationally to folding co-translationally--a result consistent with previous experimental studies. Our approach explains essential features of co-translational folding curves and predicts how varying the translation rate at different codon positions along a transcript's coding sequence affects this self-assembly process.
authors.affiliation: Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nissley
authors.affiliation: Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Ajeet K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Ahmed
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Friedrich
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Kramer
authors.affiliation: Center for Molecular Biology of the University of Heidelberg (ZMBH), Im Neuenheimer Feld 282, Heidelberg D-69120, Germany.|German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
authors.affiliation: Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA.|Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002460:Cell Line; D003062:Codon; D007700:Kinetics; D014176:Protein Biosynthesis; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; D011506:Proteins