Codon bias and the folding dynamics of the cystic fibrosis transmembrane conductance regulator

Cellular & Molecular Biology Letters

Arkadiusz Piotrowski¹  Aleksandra Sobolewska¹  Anna Janaszak Jasiecka¹  Steven M. Rowe⁴  Briana Vecchio-Pagan²  Rafal Bartoszewski¹  Sadis Matalon³  Garry R. Cutting²  James F. Collawn⁷  Lianwu Fu⁷  Sylwia Bartoszewska⁵  Jaroslaw Króliczewski⁶ 

[1] Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland$$;Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA$$;Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, USA$$Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA$$Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, Birmingham, USA$$;Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA$$Departments of Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, USA$$Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, Birmingham, USA$$;Department of Inorganic Chemistry, Medical University of Gdansk, Gdansk, Poland$$;Laboratory of Chemical Biology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland$$;Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA$$Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, Birmingham, USA$$

关键词: Synonymous mutations;    Single nucleotide polymorphism (SNP);    Codon usage;    mRNA folding;    Translation rate;    CFTR;   

DOI  :  10.1186/s11658-016-0025-x

学科分类：分子生物学，细胞生物学和基因

来源: Uniwersytet Wroclawski * Wydzial Biotechnologii / University of Wroclaw, Faculty of Biotechnology

【 摘 要 】

Synonymous or silent mutations are often overlooked in genetic analyses for disease-causing mutations unless they are directly associated with potential splicing defects. More recent studies, however, indicate that some synonymous single polynucleotide polymorphisms (sSNPs) are associated with changes in protein expression, and in some cases, protein folding and function. The impact of codon usage and mRNA structural changes on protein translation rates and how they can affect protein structure and function is just beginning to be appreciated. Examples are given here that demonstrate how synonymous mutations alter the translational kinetics and protein folding and/or function. The mechanism for how this occurs is based on a model in which codon usage modulates the translational rate by introducing pauses caused by nonoptimal or rare codons or by introducing changes in the mRNA structure, and this in turn influences co-translational folding. Two examples of this include the multidrug resistance protein (p-glycoprotein) and the cystic fibrosis transmembrane conductance regulator gene (CFTR). CFTR is also used here as a model to illustrate how synonymous mutations can be examined using in silico predictive methods to identify which sSNPs have the potential to change protein structure. The methodology described here can be used to help identify “non-silent” synonymous mutations in other genes.

【 授权许可】

Unknown