Zinc finger structure determination by NMR: Why zinc fingers can be a handful

Neuhaus, David

doi:10.1016/j.pnmrs.2022.07.001

Cited by 23 publications

(14 citation statements)

References 283 publications

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“…The data are consistent with a ββα secondary structure, typical of the classical ZNF folding motif (Klug 2010; Lee et al . 1989; Neuhaus 2022; Padjasek et al . 2020).…”

Section: Resultsmentioning

confidence: 99%

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

Rua,

Alexandrescu

2024

Preprint

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Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc-fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711 it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal ligand. The Z7 domain adopts a stable tertiary structure upon metal binding. The NMR structure of Zn2+-bound Z7 shows the classical ββα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenyalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on the Kd values for Zn2+and Co2+and retain the high thermal stability of the WT domain above 80oC. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors. Our findings that Z7 can fold with only a subset of three metal ligands suggests the recent view that most everything about protein structure can be predicted through homology modeling might be premature for at least the resilient and versatile zinc-finger motif.

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“…The data are consistent with a ββα secondary structure, typical of the classical ZNF folding motif (Klug 2010; Lee et al . 1989; Neuhaus 2022; Padjasek et al . 2020).…”

Section: Resultsmentioning

confidence: 99%

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

Rua,

Alexandrescu

2024

Preprint

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“…A review by Neuhaus 2022 gives an account of the discovery of Zn finger (ZF) proteins, their varied structures, and DNA, RNA, and protein binding [ 118 ]. The author gives a loose description of ZF proteins as those with domains whose structures and functions have been stabilized by one or more tetrahedrally co-ordinated Zn 2+ ions bound to different combinations of cysteine (C) and histidine (H) residues (typically two Cs and two Hs) without getting involved in its enzyme chemistry.…”

Section: Resultsmentioning

confidence: 99%

Zinc in Prostate Health and Disease: A Mini Review

Karunasinghe

2022

Biomedicines

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Introduction-With the high global prevalence of prostate cancer and associated mortalities, it is important to enhance current clinical practices for better prostate cancer outcomes. The current review is towards understanding the value of Zn towards this mission. Method-General information on Zn in biology and multiple aspects of Zn involvement in prostate health and disease were referred to in PubMed. Results-The most influential feature of Zn towards prostate health is its ability to retain sufficient citrate levels for a healthy prostate. Zn deficiencies were recorded in serum, hair, and prostate tissue of men with prostate cancer compared to non-cancer controls. Zn gut absorption, albumin binding, and storage compete with various factors. There are multiple associations of Zn cellular influx and efflux transporters, Zn finger proteins, matrix metalloproteinases, and Zn signaling with prostate cancer outcomes. Such Zn marker variations associated with prostate cancer recorded from biological matrices may improve algorithms for prostate cancer screening, prognosis, and management when coupled with standard clinical practices. Discussion-The influence of Zn in prostatic health and disease is multidimensional, therefore more personalized Zn requirements may be beneficial. Several opportunities exist to utilize and improve understanding of Zn associations with prostate health and disease.

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“…First, most Reclovirid "orphan" proteins contain membrane-spanning segments at their N-termini and internal trans-membrane regions that may direct these proteins to the ER membranes. Second, these proteins possess putative zinc-finger motifs, which in many cases are known to participate in nucleic acid binding (including ssRNA binding) [20][21][22]. Interestingly, the Rice yellow mottle virus protein with movement and silencing suppression functions has been shown to Quite interestingly, CDD analysis of non-replicative proteins of Reclovirids revealed that the largest of these proteins (668 aa in length), the Astragalus canadensis VLRA ORF2 protein, contains a domain of the Mpp10 protein family (COG5384) (positions 205-465, e-value 2.84e−03).…”

Section: Discussionmentioning

confidence: 99%

“…First, most Reclovirid "orphan" proteins contain membrane-spanning segments at their N-termini and internal trans-membrane regions that may direct these proteins to the ER membranes. Second, these proteins possess putative zinc-finger motifs, which in many cases are known to participate in nucleic acid binding (including ssRNA binding) [20][21][22]. Interestingly, the Rice yellow mottle virus protein with movement and silencing suppression functions has been shown to contain two essential zinc-finger motifs [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

Predicted Membrane-Associated Domains in Proteins Encoded by Novel Monopartite Plant RNA Viruses Related to Members of the Family Benyviridae

Morozov,

Lezzhov,

Solovyev

2023

IJMS

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As a continuation of our previous work, in this paper, we examine in greater detail the genome organization and some protein properties of the members of a potential group named Reclovirids and belonging to Benyviridae-related viruses. It can be proposed that the single-component Reclovirid genomes encode previously undiscovered transport genes. Indeed, analysis of the coding potential of these novel viral genomes reveals one or more cistrons ranging in size from 40 to 80 to about 600 codons, located in the 3′-terminal region of the genomic RNA, encoding proteins with predicted hydrophobic segments that are structurally diverse among Reclovirids and have no analogues in other plant RNA viruses. Additionally, in many cases, the possible methyltransferase domain of Reclovirid replicases is preceded by membrane-embedded protein segments that are not present in annotated members of the Benyviridae family. These observations suggest a general association of most Reclovirid proteins with cell membranes.

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Zinc finger structure determination by NMR: Why zinc fingers can be a handful

Cited by 23 publications

References 283 publications

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

Zinc in Prostate Health and Disease: A Mini Review

Predicted Membrane-Associated Domains in Proteins Encoded by Novel Monopartite Plant RNA Viruses Related to Members of the Family Benyviridae

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