Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Issue 1 (19th January 2023)

• Record Type: Journal Article
• Authors: Sun, Shuhong; Wang, Chao; Zhao, Pei; Kline, Gabe M.; Grandjean, Julia M.D.; Jiang, Xin; Labaudiniere, Richard; Wiseman, R. Luke; Kelly, Jeffery W.; Balch, William E.
• Is Part Of: Cell chemical biology. Volume 30:Issue 1(2023)
• Page Start: 22
• Page End: 42.e5
• Publication Date: 2023-01-19
• Subjects: protein folding -- protein misfolding disease -- protein aggregation -- alpha-1 antitrypsin -- alpha-1 antitrypsin deficiency -- genetic variation -- proteostasis -- unfolded protein response (UPR) -- activating transcription factor 6 (ATF6) -- pharmacological ATF6 activators -- chaperones -- Gaussian process -- machine learning -- precision medicine; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.12.004
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Genetic variation in alpha-1 antit rypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine. Graphical abstract: Highlights: ATF6 activators improve monomer secretion and activity for pathogenic AAT variants ATF6 activators reduce polymer accumulation for pathogenic AAT variants including Z Gaussian process (GP) captures the critical role of gate area for AAT-specific activity GP describes residue-by-residue conversion of the fold in response to proteostasis Abstract : Using genetic variation in the human population through Gaussian process (GP)-based machine learning, Sun et al. capture the residue-by-residue conversion of the pathogenic alpha-1 antitrypsin (AAT) fold into a functional protein with improved activity and reduced polymer by pharmacological activation of the ATF6 branch of unfolded protein response (UPR).