PAD6 (human, recombinant)

Protein arginine deiminase 6 (PAD6) is a homodimeric guanidine-modifying enzyme belonging to the amidinotransferase superfamily.¹ It is a calcium-dependent enzyme that catalyzes the post-translational modification of target proteins by converting arginine to citrulline. PAD6 is expressed in mammalian oocytes, sperm cells, and early embryos.² In mammalian oocytes and early embryo cytoplasm, its expression is localized to cytoskeletal sheets, dynamic structures containing various keratins, which are major targets for citrullination. PAD6^-/- oocytes exhibit reduced microtubule acetylation and defective organelle positioning and redistribution, suggesting a role for PAD6 in regulating microtubule-mediated organelle movement and positioning.³ PAD6^-/- female, but not male, mice are infertile due to a reduction of de novo protein synthesis, cytoskeletal sheet formation, and ribosomal RNA which induces arrest of zygote development at the two-cell stage.^2,4 PAD6 is regulated by newborn ovary homeobox (Nobox), as its promoter contains a Nobox DNA-binding element (NBE) and expression and activity of PAD6 are decreased in Nobox^-/- mouse ovaries.⁵ In human females, homozygous nonsense mutations and compound-heterozygous mutations in PAD6 induce early embryonic arrest following in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).⁶

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1. Bicker, K.L., and Thompson, P.R. The protein arginine deiminases: Structure, function, inhibition, and disease. Bioplymers 99(2), 155-163 (2013).

2. Esposito, G., Vitale, A.M., Leijten, F.P., et al. Peptidylarginine deiminase (PAD) 6 is essential for oocyte cytoskeletal sheet formation and female fertility. Mol. Cell Endocrinol. 273(1-2), 25-31 (2007).

3. Kan, R., Yurttas, P., Kim, B., et al. Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices. Dev. Biol. 350(2), 311-322 (2011).

4. Liu, X., Morency, E., Li, T., et al. Role for PADI6 in securing the mRNA-MSY2 complex to the oocyte cytoplasmic lattices. Cell Cycle 16(4), 360-366 (2017).

5. Choi, M., Lee, O.H., Jeon, S., et al. The oocyte-specific transcription factor, Nobox, regulates the expression of Pad6, a peptidylarginine deiminase in the oocyte. FEBS Lett. 584(16), 3629-3634 (2010).

6. Xu, Y., Shi, Y., Fu, J., et al. Mutations in PADI6 cause female infertility characterized by early embryonic arrest. Am. J. Hum. Genet. 99(3), 744-752 (2016).