Regulation of classical zinc fingers for neuronal signaling in the central nervous system

Zinc finger (ZF) proteins are well-known for their regulatory functions in the central dogma, and their structural domains serve as promising scaffolds for the study of neurodegenerative diseases. These proteins often contain multiple ZF domains, enabling interactions with target molecules that regulate transcription and translation. The Cys₂His₂ (C₂H₂) type ZF domains, found in the brain, are associated with long- and short-term memory, neuronal differentiation and development, and other physiological processes. The classical C-X₂-C-X₁₂-H-X₃-H type ZF domains have been detected in studies of Parkinson's disease (PD) and are closely linked to biological pathways involved in a wide range of neurodegenerative diseases. In this review, we introduce three ZF proteins expressed in the brain: Parkin-interacting substrate (PARIS), zinc finger and BTB domain-containing 20 (ZBTB20), and zinc finger protein 18 (ZNF18). We explore the structural and functional roles of these ZF proteins in the brain. Each of these proteins contains more than four ZF domains, as well as functional domains such as KRAB, BTB, and SCAN, which perform modular roles independently of the ZF domains. Biophysical studies of PARIS have demonstrated that its classical three-ZF domain, PARIS(ZF2–4), forms hydrogen bonds with insulin response sequences (IRSs) with high specificity (K_d = 38.9 ± 2.4 nM). Metal coordination studies showed that PARIS binds Co²⁺ with high affinity (K_d = 49.1 ± 7.7 nM), more strongly than other ZF domains, and it also coordinates with other xenobiotic metal ions such as Fe²⁺ and Ni²⁺. Although Zn²⁺–PARIS(ZF2–4) binds specifically to IRSs, Fe²⁺–, Fe³⁺– or Co²⁺–PARIS(ZF2–4) cannot, due to distortions in the ZF domain structure that disrupt hydrogen bonding. These brain-specific ZF domains exhibit common patterns, with similar numbers of ZF domains and sequence homology at the C-terminus, whereas both the ZF domains and N-terminal protein–protein interaction domains contribute to their functional versatility. Elucidating the structure and function of these classical ZF proteins offers promising avenues for the treatment of diverse brain disorders, including Alzheimer's disease, PD, and autism spectrum disorder.