Research Institute for Microbial Diseases, University, Suita, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3850-5. doi: 10.1073/pnas.1117963109. Epub 2012 Feb 22.
A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for both sperm migration from the uterus into the oviduct and sperm primary binding to the zona pellucida (ZP). Here we show that the testis-specific protein disulfide isomerase homolog (PDILT) cooperates with the testis-specific calreticulin-like chaperone, calsperin (CALR3), in the endoplasmic reticulum and plays an indispensable role in the disulfide-bond formation and folding of ADAM3. Pdilt(-/-) mice were male infertile because ADAM3 could not be folded properly and transported to the sperm surface without the PDILT/CALR3 complex. Peculiarly we find that not only Pdilt(-/-), but also Adam3(-/-), spermatozoa effectively fertilize eggs when the eggs are surrounded in cumulus oophorus. These findings reveal that ADAM3 requires testis-specific private chaperones to be folded properly and that the principle role of ADAM3 is for sperm migration into the oviduct but not for the fertilization event. Moreover, the importance of primary sperm ZP binding, which has been thought to be a critical step in mammalian fertilization, should be reconsidered.
解整合素金属蛋白酶 3（ADAM3）是一种精子膜蛋白，对于精子从子宫迁移到输卵管以及精子与透明带（ZP）的初次结合都至关重要。在这里，我们表明睾丸特异性蛋白二硫键异构酶同源物（PDILT）与睾丸特异性钙网蛋白样伴侣 calsperin（CALR3）在 ER 中合作，并在 ADAM3 的二硫键形成和折叠中发挥不可或缺的作用。由于没有 PDILT/CALR3 复合物，ADAM3 无法正确折叠并转运到精子表面，因此 Pdilt(-/-) 小鼠是雄性不育的。有趣的是，我们发现不仅是 Pdilt(-/-)，而且 Adam3(-/-)，当卵子被卵丘包围时，精子也能有效地受精卵子。这些发现揭示了 ADAM3 需要睾丸特异性的专用伴侣来正确折叠，并且 ADAM3 的主要作用是用于精子迁移到输卵管，而不是受精事件。此外，应该重新考虑被认为是哺乳动物受精关键步骤的初级精子 ZP 结合的重要性。
