The RING domain of human promyelocytic leukemia protein (PML)

Huang, Shu Yu; Chang, Chi‐Fon; Fang, Pei Ju; Naik, Mandar T.; Güntert, Peter; Shih, Hsiu Ming; Huang, Tai Huang

doi:10.1007/s10858-015-9901-3

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…1a , Supplementary Figure 1a–e ). Similar to previous RING structures 16 , 24 , the folding of PML RING 49–104 is coordinated by two Zn ions, but in contrast with previous studies, PML RING leads tetrameric complexes. Within a tetramer, each PML subunit adopts a balloon shape configuration with two distinct sub-domains.…”

Section: Resultssupporting

confidence: 83%

RING tetramerization is required for nuclear body biogenesis and PML sumoylation

Wang¹,

Benhenda²,

Wu³

et al. 2018

Nat Commun

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ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.

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Section: Resultssupporting

confidence: 83%

RING tetramerization is required for nuclear body biogenesis and PML sumoylation

Wang¹,

Benhenda²,

Wu³

et al. 2018

Nat Commun

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“…An outlier with respect to RING oligomerization is TRIM19 (PML), which forms a 'torus-shaped' tetramer. Despite being described as monomeric in solution by an NMR study (PDB: 2MWX), it crystallizes in a tetrameric form (PDB: 5YUF) via a pattern of conserved TRIM19-specific residues ( Figure 2B) [32,52]. Tetramerization is suggested to be a requisite for its observed sumoylation activity and formation of nuclear bodies and involves residues that are highly conserved amongst TRIM19 orthologs.…”

Section: Trims With Unusual Oligomeric Ringsmentioning

confidence: 99%

Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases

Fiorentini

Esposito

Rittinger

2020

Biochemical Society Transactions

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TRIM proteins form a protein family that is characterized by a conserved tripartite motif domain comprising a RING domain, one or two B-box domains and a coiled-coil region. Members of this large protein family are important regulators of numerous cellular functions including innate immune responses, transcriptional regulation and apoptosis. Key to their cellular role is their E3 ligase activity which is conferred by the RING domain. Self-association is an important characteristic of TRIM protein activity and is mediated by homodimerization via the coiled-coil region, and in some cases higher order association via additional domains of the tripartite motif. In many of the TRIM family proteins studied thus far, RING dimerization is an important prerequisite for E3 ligase enzymatic activity though the propensity of RING domains to dimerize differs significantly between different TRIMs and can be influenced by other regions of the protein.

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“…However, the obtained structural data for the PML RING monomer (2MWX.pdb) revealed a discrepancy, as there was no detected interaction between the FQF loop and its corresponding L73 pocket (Figure 4A) [64]. Analyzing the crystallization conditions, we noted that both the 1BOR and 2MWX structures were obtained under the same pH and buffer conditions, but the 1BOR sample consisted of a synthetic peptide refolded in the presence of Zn 2+ , while 2MWX was expressed and purified directly from E. coli in the presence of 20 µM Zn 2+ [64]. We decided to examine the positions of F52 and L73 in the generated AlphaFold2 prediction model and discovered that the FQF loop could be concealed within a hydrophobic pocket between the B1-and B2-box domains (F52 is in proximity to L174 and L178, Figure 4B).…”

Section: Ring Domain Pml: Dimerization and Tetramerizationmentioning

confidence: 95%

“…On the other hand, since in the tetrameric RING structure, the FQF loop interacts with the hydrophobic pocket of another subunit, a hypothesis emerged regarding the possible activation (priming) of PML monomer prior to dimerization [4]. However, the obtained structural data for the PML RING monomer (2MWX.pdb) revealed a discrepancy, as there was no detected interaction between the FQF loop and its corresponding L73 pocket (Figure 4A) [64]. Analyzing the crystallization conditions, we noted that both the 1BOR and 2MWX structures were obtained under the same pH and buffer conditions, but the 1BOR sample consisted of a synthetic peptide refolded in the presence of Zn 2+ , while 2MWX was expressed and purified directly from E. coli in the presence of 20 µM Zn 2+ [64].…”

Section: Ring Domain Pml: Dimerization and Tetramerizationmentioning

confidence: 98%

PML Body Biogenesis: A Delicate Balance of Interactions

Silonov,

Smirnov,

Kuznetsova

et al. 2023

IJMS

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PML bodies are subnuclear protein complexes that play a crucial role in various physiological and pathological cellular processes. One of the general structural proteins of PML bodies is a member of the tripartite motif (TRIM) family—promyelocytic leukemia protein (PML). It is known that PML interacts with over a hundred partners, and the protein itself is represented by several major isoforms, differing in their variable and disordered C-terminal end due to alternative splicing. Despite nearly 30 years of research, the mechanisms underlying PML body formation and the role of PML proteins in this process remain largely unclear. In this review, we examine the literature and highlight recent progress in this field, with a particular focus on understanding the role of individual domains of the PML protein, its post-translational modifications, and polyvalent nonspecific interactions in the formation of PML bodies. Additionally, based on the available literature, we propose a new hypothetical model of PML body formation.

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The RING domain of human promyelocytic leukemia protein (PML)

Cited by 5 publications

References 25 publications

RING tetramerization is required for nuclear body biogenesis and PML sumoylation

RING tetramerization is required for nuclear body biogenesis and PML sumoylation

Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases

PML Body Biogenesis: A Delicate Balance of Interactions

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