Open AccessStructural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease
Author(s) -
Yoshiyuki Toyama,
Robert W. Harkness,
Lewis E. Kay
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2203172119
Subject(s) - biophysics , trimer , protease , protein folding , nuclear magnetic resonance spectroscopy , protein structure , chemistry , plasma protein binding , peptide , binding site , biochemistry , protein–protein interaction , biology , enzyme , stereochemistry , dimer , organic chemistry
Significance Protein aggregates are often toxic, leading to impaired cellular activities and disease. The human HtrA2 trimeric enzyme cleaves such aggregates, and mutations in HtrA2 are causative for various neurodegenerative disorders, such as Parkinson’s disease and essential tremor. The mechanism by which cleavage occurs has been studied using small peptides, but little information is available as to how HtrA2 protects cells from the pathologic effects of aggregation involving protein molecules that can form well-folded structures. Using solution NMR spectroscopy, we investigated the structural dynamics of the interaction between HtrA2 and a model protein substrate, demonstrating that HtrA2 preferentially binds to an unfolded substrate ensemble and providing insights into how HtrA2 function is regulated.