7YAB

Solution structure of zinc finger domain 1 of human ZFAND1

Summary for 7YAB

• Entry DOI: 10.2210/pdb7yab/pdb
• Descriptor: AN1-type zinc finger protein 1, ZINC ION (2 entities in total)
• Functional Keywords: an1-type zinc finger protein, zfand1, proteasome, stress granule, proteostasis, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 5101.34

Authors

Fang, P.J.,Lai, C.H.,Ko, K.T.,Chang, C.F.,Hsu, S.T.D. (deposition date: 2022-06-27, release date: 2023-06-28, Last modification date: 2024-11-20)

Primary citation

Lai, C.H.,Ko, K.T.,Fan, P.J.,Yu, T.A.,Chang, C.F.,Draczkowski, P.,Hsu, S.D.
Structural insight into the ZFAND1-p97 interaction involved in stress granule clearance.
J.Biol.Chem., 300:107230-107230, 2024

PubMed Abstract: Arsenite-induced stress granule (SG) formation can be cleared by the ubiquitin-proteasome system aided by the ATP-dependent unfoldase p97. ZFAND1 participates in this pathway by recruiting p97 to trigger SG clearance. ZFAND1 contains two An1-type zinc finger domains (ZF1 and ZF2), followed by a ubiquitin-like domain (UBL); but their structures are not experimentally determined. To shed light on the structural basis of the ZFAND1-p97 interaction, we determined the atomic structures of the individual domains of ZFAND1 by solution-state NMR spectroscopy and X-ray crystallography. We further characterized the interaction between ZFAND1 and p97 by methyl NMR spectroscopy and cryo-EM. N spin relaxation dynamics analysis indicated independent domain motions for ZF1, ZF2, and UBL. The crystal structure and NMR structure of UBL showed a conserved β-grasp fold homologous to ubiquitin and other UBLs. Nevertheless, the UBL of ZFAND1 contains an additional N-terminal helix that adopts different conformations in the crystalline and solution states. ZFAND1 uses the C-terminal UBL to bind to p97, evidenced by the pronounced line-broadening of the UBL domain during the p97 titration monitored by methyl NMR spectroscopy. ZFAND1 binding induces pronounced conformational heterogeneity in the N-terminal domain of p97, leading to a partial loss of the cryo-EM density of the N-terminal domain of p97. In conclusion, this work paved the way for a better understanding of the interplay between p97 and ZFAND1 in the context of SG clearance.

PubMed: 38537699
DOI: 10.1016/j.jbc.2024.107230

Experimental method

SOLUTION NMR