Structural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease

Abstract

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.