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Review
. 2023 Nov 24;24(23):16702.
doi: 10.3390/ijms242316702.

PML Body Biogenesis: A Delicate Balance of Interactions

Sergey A Silonov  1 , Eugene Y Smirnov  1 , Irina M Kuznetsova  1 , Konstantin K Turoverov  1 , Alexander V Fonin  1
Affiliations
Review

PML Body Biogenesis: A Delicate Balance of Interactions

Sergey A Silonov et al. Int J Mol Sci. .

Abstract

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.

Keywords: PML-bodies; SUMO/SIM; TRIM domain; biomolecular condensates; intrinsically disordered protein; liquid–liquid phase separation; membraneless organelle.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PML isoforms and mRNA structures are produced by alternative splicing. The PML gene exons are shown in blue, with rectangle sizes proportional to the nucleotide sequence lengths. The alternative splicing-derived mRNAs are represented in gray. The mRNA-translated regions are shown in red, while the untranslated regions (UTRs) are indicated in the remaining regions. The asterisks indicate that intron retention occurs in PML-III, -V, and -VI [6]. The alignment data were obtained using the NCBI database.
Figure 2
Figure 2
AlphaFold2 prediction analysis for the major PML isoforms. The center panel shows the overlay of structures ranging from amino acid residues 34–456, generated in UCSF ChimeraX [63]. For PML-II (top right panel), an identified alpha-helix in the region of 650–672 aa is shown. Pink arrows indicate the predicted alpha-helix at amino acid residues 421–430, corresponding to exon 5 of the PML gene.
Figure 3
Figure 3
Known structural models based on crystallographic studies and AlphaFold2 prediction (AF-P29590-F1)—Panel (A). Proposed pathways of PML protein oligomerization—Panel (B). Structures depicted using UCSF ChimeraX [63]: RING monomers, dimers, and tetramers (5YUF.pdb); B1-box antiparallel dimer (6IMQ.pdb); B1-box parallel dimer (2MVW.pdb). The arrows indicate potential pathways of PML oligomerization.
Figure 4
Figure 4
Structure of the PML RING domain. Panel (A): Comparison of crystal structures obtained from the Protein Data Bank (1BOR.pdb—green, 2MWX.pdb—red). Panel (B): Position of the FQF loop (F52/F54 tail, shown in red) in the predicted AlphaFold2 structure of PML. It is demonstrated that the FQF loop is concealed within the hydrophobic pocket of the B1- and B2-box domains. Images were generated using UCSF ChimeraX [63].
Figure 5
Figure 5
Comparison of TRIM family B-box domains. Panel (A)—Overlay of PML B1- and B2-box domain structures (blue, cyan—AlphaFold2 prediction) and crystal structures of B-box domains: TRIM63 (3DDT.pdb), TRIM5α (5K3Q.pdb), TRIM41 (2EGM.pdb), and TRIM54 (3Q1D.pdb). Panel (B)—Sequence alignment of B-box domains, with β-sheets and α-helices displayed on top. Colors correspond to the default Clustal color scheme. Structure comparison was performed using ChimeraX, sequence alignment was performed using ClustalW [71], and visualization was conducted using Jalview [72].
Figure 6
Figure 6
Hypothetical model of PML body formation. Shown are the stages of PML protein maturation through liquid–liquid phase separation (LLPS), followed by RING, B1–B2 box domain (B1, B2) dimerization, and coiled-coil (CC) domain dimerization to form the hexameric structure. Confocal microscopy data from our group’s studies [22,60] are presented. It is shown that smaller PML bodies exchange their components with the nucleoplasm more rapidly (as evidenced by fluorescence recovery after photobleaching (FRAP) recovery rate of ~80%), while larger, ‘mature’ PML bodies exchange more slowly (FRAP recovery of about ~30%). Super-resolution SIM microscopy data are taken from an open research article by Li Chuang and colleagues [59].
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