Protein cysteine residues in redox-sensitive signaling proteins

Protein cysteine residues in redox-sensitive signaling proteins serve as critical sensors for cellular oxidative stress and electrophilic signals [6, 12]. These specific residues often exhibit a lowered pKa, allowing them to exist as reactive thiolate anions at physiological pH, which facilitates post-translational modifications such as S-nitrosylation, S-glutathionylation, and disulfide formation [9, 10]. Such modifications act as "thiol switches" that regulate the activity of key proteins, including transcription factors like Nrf2 and NF-κB, as well as various protein kinases and phosphatases [8, 11, 14]. In many pathological states, including cancer and chronic inflammation, the redox balance is disrupted, leading to aberrant signaling through these cysteine-mediated pathways [1, 11]. Modern drug discovery increasingly exploits these reactive sites through the design of covalent inhibitors (e.g., afatinib, sotorasib) that specifically target a cysteine residue within a binding pocket to achieve high potency and prolonged duration of action [1, 4]. However, the inherent reactivity of these residues necessitates careful design to avoid widespread off-target effects and potential immunogenicity [1, 4].

Other names

Redox-sensitive cysteinesReactive cysteinesThiol switchesProtein thiolsCysteine redoxome

Covalent modification of reactive thiol groups (thiolates) to modulate protein activity, stability, or signaling.