Nomikos, Michail, Stamatiadis, Panagiotis, Sanders, Jessica Rose, Beck, Konrad  ORCID: https://orcid.org/0000-0001-5098-9484, Calver, Brian Lewis, Buntwal, Luke, Lofty, Morgan, Sideratou, Zili, Swann, Karl ORCID: https://orcid.org/0000-0002-4355-1449 and Lai, Francis Anthony ORCID: https://orcid.org/0000-0003-2852-8547
2017.
Male infertility-linked point mutation reveals a vital binding role for the C2 domain of sperm PLCζ.
Biochemical Journal
474
(6)
, pp. 1003-1016.
10.1042/BCJ20161057
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Abstract
Sperm-specific phospholipase C zeta (PLCζ) is widely considered to be the physiological stimulus that evokes intracellular calcium (Ca2+) oscillations that are essential for the initiation of egg activation during mammalian fertilisation. A recent genetic study reported a male infertility case that was directly associated with a point mutation in the PLCζ C2 domain, where an isoleucine residue had been substituted with a phenylalanine (I489F). Here, we have analysed the effect of this mutation on the in vivo Ca2+ oscillation-inducing activity and the in vitro biochemical properties of human PLCζ. Microinjection of cRNA or recombinant protein corresponding to PLCζI489F mutant at physiological concentrations completely failed to cause Ca2+ oscillations and trigger development. However, this infertile phenotype could be effectively rescued by microinjection of relatively high (non-physiological) amounts of recombinant mutant PLCζI489F protein, leading to Ca2+ oscillations and egg activation. Our in vitro biochemical analysis suggested that the PLCζI489F mutant displayed similar enzymatic properties, but dramatically reduced binding to PI(3)P and PI(5)P-containing liposomes compared with wild-type PLCζ. Our findings highlight the importance of PLCζ at fertilisation and the vital role of the C2 domain in PLCζ function, possibly due to its novel binding characteristics.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences Schools > Dentistry |
| Uncontrolled Keywords: | Male infertility, Fertilization, Sperm, Phospholipase C zeta (PLC), calcium oscillations, C2 domain |
| Publisher: | Biochemical Society |
| ISSN: | 0264-6021 |
| Date of First Compliant Deposit: | 25 May 2017 |
| Date of Acceptance: | 20 January 2017 |
| Last Modified: | 06 Nov 2024 17:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/100874 |
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