Identification of an atypical interaction site in the BTB domain of the MYC-interacting zinc-finger protein 1

Orth, Barbara; Sander, Bodo; Möglich, Andreas; Diederichs, Kay; Eilers, Martin; Lorenz, Sonja

doi:10.1016/j.str.2021.06.005

Cited by 10 publications

(19 citation statements)

References 64 publications

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“…The plasmids encoding the HECT domain of HUWE1 (residues 3993–4374) and E6AP (495–852); the extended (3843–4374; for MIZ1 ubiquitination in vitro ) version of HUWE1 HECT ; the C-lobe of E6AP (741–852); C-terminally HA-His 6 -tagged MIZ1 (1–282; containing ubiquitination sites); UBE2L3, UBA1, and ubiquitin , were previously described. The intein-chitin-binding domain (CBD)-tagged ubiquitin plasmid was kindly provided by David Komander.…”

Section: Methodsmentioning

confidence: 99%

“…The HECT domain of HUWE1, NEDD4, and E6AP, respectively, was purified from E . coli LOBSTR RIL (Kerafast) by nickel-affinity and size-exclusion chromatography (SEC) following published strategies. , The respective C-lobes, UBA1, UBE2L3, and ubiquitin were prepared as described, , likewise MIZ1 (1–282). The preparation of the ubiquitin-HUWE1 HECT complex was also guided by published protocols .…”

Section: Methodsmentioning

confidence: 99%

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Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe

et al. 2021

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Ubiquitin activity-based probes have proven invaluable in elucidating structural mechanisms in the ubiquitin system by stabilizing transient macromolecular complexes of deubiquitinases, ubiquitin-activating enzymes, and the assemblies of ubiquitin-conjugating enzymes with ubiquitin ligases of the RING-Between-RING and RING-Cysteine-Relay families. Here, we demonstrate that an activity-based probe, ubiquitin-propargylamine, allows for the preparative reconstitution and structural analysis of the interactions between ubiquitin and certain HECT ligases. We present a crystal structure of the ubiquitin-linked HECT domain of HUWE1 that defines a catalytically critical conformation of the C-terminal tail of the ligase for the transfer of ubiquitin to an acceptor protein. Moreover, we observe that ubiquitin-propargylamine displays selectivity among HECT domains, thus corroborating the notion that activity-based probes may provide entry points for the development of specific, active site-directed inhibitors and reporters of HECT ligase activities.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe

et al. 2021

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“…As well as functioning as transcription factors, numbers of ZFPs that can induce protein interactions have also been identified in recent years [ 58 ]. For example, the striated muscle RING zinc finger protein (SMRZ) is a novel human striated muscle ZFP which has a ring domain at its N-terminal.…”

Section: Biological Functions Of Zinc Finger Proteinsmentioning

confidence: 99%

Structures and biological functions of zinc finger proteins and their roles in hepatocellular carcinoma

Han

Zhang

et al. 2022

Biomark Res

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Zinc finger proteins are transcription factors with the finger domain, which plays a significant role in gene regulation. As the largest family of transcription factors in the human genome, zinc finger (ZNF) proteins are characterized by their different DNA binding motifs, such as C2H2 and Gag knuckle. Different kinds of zinc finger motifs exhibit a wide variety of biological functions. Zinc finger proteins have been reported in various diseases, especially in several cancers. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide, especially in China. Most of HCC patients have suffered from hepatitis B virus (HBV) and hepatitis C virus (HCV) injection for a long time. Although the surgical operation of HCC has been extremely developed, the prognosis of HCC is still very poor, and the underlying mechanisms in HCC tumorigenesis are still not completely understood. Here, we summarize multiple functions and recent research of zinc finger proteins in HCC tumorigenesis and progression. We also discuss the significance of zinc finger proteins in HCC diagnosis and prognostic evaluation.

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“…If so, could the non-symmetrical lateral grooves of BTB heterodimers provide a mechanism of altered specificity for co-repressors? Besides the BTB domain lateral groove interactions assisted by lower β-sheet extensions, exemplified by the BCOR/NCOR1/NCOR2 interactions with BCL6, a novel interaction site on BTB domains was recently revealed ( Orth et al, 2021 ). The interaction of a β-strand containing peptide from HUWE1 with the flexible B3 region of MIZ1 can result in an upper β-sheet extension.…”

Section: Discussionmentioning

confidence: 99%

Sibling rivalry among the ZBTB transcription factor family: homodimers versus heterodimers

et al. 2022

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The BTB domain is an oligomerization domain found in over 300 proteins encoded in the human genome. In the family of BTB domain and zinc finger–containing (ZBTB) transcription factors, 49 members share the same protein architecture. The N-terminal BTB domain is structurally conserved among the family members and serves as the dimerization site, whereas the C-terminal zinc finger motifs mediate DNA binding. The available BTB domain structures from this family reveal a natural inclination for homodimerization. In this study, we investigated the potential for heterodimer formation in the cellular environment. We selected five BTB homodimers and four heterodimer structures. We performed cell-based binding assays with fluorescent protein–BTB domain fusions to assess dimer formation. We tested the binding of several BTB pairs, and we were able to confirm the heterodimeric physical interaction between the BTB domains of PATZ1 and PATZ2, previously reported only in an interactome mapping experiment. We also found this pair to be co-expressed in several immune system cell types. Finally, we used the available structures of BTB domain dimers and newly constructed models in extended molecular dynamics simulations (500 ns) to understand the energetic determinants of homo- and heterodimer formation. We conclude that heterodimer formation, although frequently described as less preferred than homodimers, is a possible mechanism to increase the combinatorial specificity of this transcription factor family.

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Identification of an atypical interaction site in the BTB domain of the MYC-interacting zinc-finger protein 1

Abstract: Highlightsd The BTB domain of MIZ1 harbors an atypical peptide binding site.d This binding site requires flexibility in a core element of the BTB fold.d Peptide binding selects for homodimers over heterodimers of the MIZ1 BTB domain.

Cited by 10 publications

References 64 publications

Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe

Reconstitution and Structural Analysis of a HECT Ligase-Ubiquitin Complex via an Activity-Based Probe

Structures and biological functions of zinc finger proteins and their roles in hepatocellular carcinoma

Sibling rivalry among the ZBTB transcription factor family: homodimers versus heterodimers

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