Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold

• Main Authors: Anglès, F. (Author), Balch, W.E (Author), Wang, C. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Subjects: amino acid sequence; article; cell surface; controlled study; covariance; endoplasmic reticulum; protein function; quality control; structure activity relation
• Online Access: View Fulltext in Publisher

 Although the impact of genome variation on the thermodynamic properties of function on the protein fold has been studied in vitro, it remains a challenge to assign these relationships across the entire polypeptide sequence in vivo. Using the Gaussian process regression based principle of Spatial CoVariance, we globally assign on a residue-by-residue basis the biological thermodynamic properties that contribute to the functional fold of CFTR in the cell. We demonstrate the existence of a thermodynamically sensitive region of the CFTR fold involving the interface between NBD1 and ICL4 that contributes to its export from endoplasmic reticulum. At the cell surface a new set of residues contribute uniquely to the management of channel function. These results support a general ‘quality assurance’ view of global protein fold management as an SCV principle describing the differential pre- and post-ER residue interactions contributing to compartmentalization of the energetics of the protein fold for function. Our results set the stage for future analyses of the quality systems managing protein sequence-to-function-to-structure broadly encompassing genome design leading to protein function in complex cellular relationships responsible for diversity and fitness in biology in response to the environment. © 2022, The Author(s).