Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Abstract

Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3‐methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

Design principles to tailor Hsp104 therapeutics

“…11-14 Notably, Hsp104 dissolves a diverse spectrum of aggregated structures, including preamyloid oligomers, disordered aggregates, phase-separated condensates, and stable amyloid or prion fibrils. 15-20 However, no exact Hsp104 homolog is found in metazoa, 11,21,22 although a related human mitochondrial AAA+ protein, Skd3, displays potent disaggregase activity, 23-26 and another AAA+ protein VCP/p97 may remodel ubiquitylated protein inclusions in the cytoplasm. 27 Nonetheless, introduction of Hsp104 or engineered variants into metazoan systems is well tolerated and can antagonize aggregation and toxicity of neurodegenerative disease proteins.…”