Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices

Jentoft, Ida M.A.; Bäuerlein, Felix J.B.; Welp, Luisa M.; Cooper, Benjamin H.; Petrovic, Arsen; So, Chun; Penir, Sarah Mae; Politi, Antonio Z.; Horokhovskyi, Yehor; Takala, Iina; Eckel, Heike; Moltrecht, Rüdiger; Lénárt, Peter; Cavazza, Tommaso; Liepe, Juliane; Brose, Nils; Urlaub, Henning; Fernández-Busnadiego, Rubén; Schuh, Melina

doi:10.1016/j.cell.2023.10.003

Cited by 33 publications

(16 citation statements)

References 133 publications

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“…Nonetheless, the accessibility and flexibility of these residues were consistent with previous data showing that both phosphorylated residues are involved in a protein-protein interaction with 14-3-3 (YWHA) (Snow et al, 2008;Rose et al, 2012). 14-3-3, a chaperone-like protein, has also recently been localized in the CPLs (Jentoft et al, 2023). We cannot rule out that interaction with 14-3-3 or any other PAD6 physiological partners could be required to activate an enzymatic activity via an unknown mechanism.…”

Section: Discussionsupporting

confidence: 90%

“…Alternatively, PAD6 might possess a non-enzymatic function in the oocyte. Indeed, several studies have shown PAD6 to be involved in CPL formation (Wright et al, 2003;Esposito et al, 2007;Jentoft et al, 2023). CPLs are highly abundant in oocytes and have long been predicted to function as a storage form for maternal contribution of ribosomes and proteins in oocytes to early embryo (Yurttas et al, 2008;Capco et al, 1993;Jentoft et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several studies have shown PAD6 to be involved in CPL formation (Wright et al, 2003;Esposito et al, 2007;Jentoft et al, 2023). CPLs are highly abundant in oocytes and have long been predicted to function as a storage form for maternal contribution of ribosomes and proteins in oocytes to early embryo (Yurttas et al, 2008;Capco et al, 1993;Jentoft et al, 2023). More recently, PAD6 has also been linked to another cytoplasmic complex, the subcortical maternal complex (SCMC) (Li et al, 2008;Kim et al, 2010), a multiprotein complex (�670-2000 kDa) essential for early embryogenesis in mouse and human (Li et al, 2008;Zhu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…On the cellular level, PAD6 is found within keratin-containing cytoplasmic lattices (CPLs) in mice (Wright et al, 2003). CPLs are proposed to serve as a storage depot for maternal proteins important for embryogenesis (Yurttas et al, 2008;Jentoft et al, 2023). Keratins, particularly cytokeratin 5 and 6, are known to be major constituents of cytoskeletal lattices (Schwarz et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity

Ranaivoson,

Bande,

Cardaun

et al. 2024

IUCrJ

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Human peptidylarginine deiminase isoform VI (PAD6), which is predominantly limited to cytoplasmic lattices in the mammalian oocytes in ovarian tissue, is essential for female fertility. It belongs to the peptidylarginine deiminase (PAD) enzyme family that catalyzes the conversion of arginine residues to citrulline in proteins. In contrast to other members of the family, recombinant PAD6 was previously found to be catalytically inactive. We sought to provide structural insight into the human homologue to shed light on this observation. We report here the first crystal structure of PAD6, determined at 1.7 Å resolution. PAD6 follows the same domain organization as other structurally known PAD isoenzymes. Further structural analysis and size-exclusion chromatography show that PAD6 behaves as a homodimer similar to PAD4. Differential scanning fluorimetry suggests that PAD6 does not coordinate Ca2+ which agrees with acidic residues found to coordinate Ca2+ in other PAD homologs not being conserved in PAD6. The crystal structure of PAD6 shows similarities with the inactive state of apo PAD2, in which the active site conformation is unsuitable for catalytic citrullination. The putative active site of PAD6 adopts a non-productive conformation that would not allow protein–substrate binding due to steric hindrance with rigid secondary structure elements. This observation is further supported by the lack of activity on the histone H3 and cytokeratin 5 substrates. These findings suggest a different mechanism for enzymatic activation compared with other PADs; alternatively, PAD6 may exert a non-enzymatic function in the cytoplasmic lattice of oocytes and early embryos.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity

Ranaivoson,

Bande,

Cardaun

et al. 2024

IUCrJ

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“…1a, Bright eld, white arrow). Cytoplasmic granules are slightly ovoid organelles formed in oocytes and zygotes 27,28 , and a previous study showed that human embryos store proteins such as chromatin modi cation factor and tubulin in cytoplasmic lattices 29 . Figure 1b shows multipolar segregation (Supplementary Movie 2).…”

Section: Live-cell Imaging Using Uorescent Labeling During the Rst Mi...mentioning

confidence: 99%

Shape of the first mitotic spindles impacts nucleation in human embryos

Ono,

Shirasawa,

Kazumasa

et al. 2024

Preprint

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During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we imaged discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigated the association between spindle shape and nuclear abnormality during the first mitosis. We observed that the first mitotic spindles varied, and low-aspect-ratio-shaped spindles tended to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observed defocusing poles in many of the first mitotic spindles, which were strongly associated with multinucleation. In addition, it has been suggested that the parental genome remains separated during the first mitosis. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.

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Regulation of Oocyte mRNA Metabolism: A Key Determinant of Oocyte Developmental Competence

Ermisch,

Wood

2024

Molecular Mechanisms Determining Mammalian Oocyte Quality

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Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices

Cited by 33 publications

References 133 publications

Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity

Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity

Shape of the first mitotic spindles impacts nucleation in human embryos

Regulation of Oocyte mRNA Metabolism: A Key Determinant of Oocyte Developmental Competence

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