Structural-functional relevance of DNAJBs in protein aggregation and associated neurodegenerative diseases

DNAJ proteins, also known as HSP40s, are co-chaperones that regulate the multifunctionality of HSP70s in maintaining cellular protein homeostasis. The heterogeneous family of DNAJ co-chaperones is classified into three classes (A, B and C), where structural diversity within the class defines their specific functions. Among three classes, the DNAJB class of co-chaperones are associated with cellular compartment-specific protein folding, disaggregation and degradation of proteins and enables effective targeting of a broad spectrum of aggregation-prone substrate proteins. The structural divergence of DNAJBs is critical for regulating disaggregation and degradation functions through specific interactions with HSP70 and substrate proteins. While the role of DNAJBs in maintaining protein homeostasis is valuable in addressing protein aggregation in neurodegenerative diseases, a limited understanding of their mechanisms and cellular functions beyond co-chaperones restricts their therapeutic applications. In this review, the mechanism of DNAJBs regulating aggregation of pathogenic proteins such as α-synuclein, tau, amyloid-β, and huntingtin are discussed. Emphasis on the selectivity of DNAJBs towards folding, disaggregation and degradation functions of HSP70, substrate selection and involvement of different structural regions are explained to provide a structural and functional understanding of DNAJB proteins. Mutations in different DNAJBs linked with several proteins aggregation-related neuronal and neuromuscular diseases are discussed. The fundamental understanding of DNAJB diversity and functionality can assist future interventions for regulating protein homeostasis and managing associated diseases.