The taste of cysteine cathepsins: analyzing specificity, aiming for function

Cysteine cathepsins are receiving large attention due to their widespread participation in physiological and pathological processes. The link between their specificity and biological function is more complex than previously anticipated. Structural analysis revealed that this complex specificity is anchored in the architecture of the active site cleft. Unlike classical proteases with well-defined specificity pockets S1, the corresponding P1 residue of a cathepsin substrate points toward solvent, precluding a clear P1-driven specificity profile. This review analyzes the evolution of cysteine cathepsin research, spanning from the initial biochemical era and the “golden age” of structural biology to contemporary high-throughput profiling, degradomics, and computational analysis. The surge in available data has reshaped our understanding, shifting from rigid active-site models toward statistically driven patterns that reflect the inherent flexibility of structure. For cysteine cathepsins, the next frontier lies in discerning redundant versus unique physiological and pathological roles. This requires integrating high-resolution localization profiles, adequate prediction models, and in situ measurements of degradation products. Such integration will mark a new era of proteolysis studies, replacing individual enzyme-centric research with a multidimensional synthesis of diverse data sources encompassing the expanding landscape of proteases and their substrates.