8SXM

NMR structure of the ZNF750 zinc finger domain, Z*

Summary for 8SXM

• Entry DOI: 10.2210/pdb8sxm/pdb
• NMR Information: BMRB: 51951
• Descriptor: Zinc finger protein 750, ZINC ION (2 entities in total)
• Functional Keywords: degenerate zinc finger, znf750, zn750, nuclear transcription factor, protein structure evolution, somatic cancer mutations, psoriasis, skin differentiation, dna-binding motif, cchc zinc finger, antiparallel bba motif, protein folding, protein structure prediction, seborrhea-like dermatosis with non-arthritic psoriasiform elements, sldp, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 3380.33

Authors

Rua, A.J.,Alexandrescu, A.T. (deposition date: 2023-05-22, release date: 2023-08-23, Last modification date: 2024-11-13)

Primary citation

Rua, A.J.,Whitehead 3rd, R.D.,Alexandrescu, A.T.
NMR structure verifies the eponymous zinc finger domain of transcription factor ZNF750.
J Struct Biol X, 8:100093-100093, 2023

PubMed Abstract: ZNF750 is a nuclear transcription factor that activates skin differentiation and has tumor suppressor roles in several cancers. Unusually, ZNF750 has only a single zinc-finger (ZNF) domain, Z*, with an amino acid sequence that differs markedly from the CCHH family consensus. Because of its sequence differences Z* is classified as degenerate, presumed to have lost the ability to bind the zinc ion required for folding. AlphaFold predicts an irregular structure for Z* with low confidence. Low confidence predictions are often inferred to be intrinsically disordered regions of proteins, which would be the case if Z* did not bind Zn. We use NMR and CD spectroscopy to show that a 25-51 segment of ZNF750 corresponding to the Z* domain folds into a well-defined antiparallel ββα tertiary structure with a pM dissociation constant for Zn and a thermal stability >80 °C. Of three alternative Zn ligand sets, Z* uses a CCHC rather than the expected CCHH ligating motif. The switch in the last ligand maintains the folding topology and hydrophobic core of the classical ZNF motif. CCHC ZNFs are typically associated with protein-protein interactions, raising the possibility that ZNF750 interacts with DNA through other proteins rather than directly. The structure of Z* provides context for understanding the function of the domain and its cancer-associated mutations. We expect other ZNFs currently classified as degenerate could be CCHC-type structures like Z*.

PubMed: 37655311
DOI: 10.1016/j.yjsbx.2023.100093

Experimental method

SOLUTION NMR