Proteins that contain a highly conserved TLDc domain (Tre2/Bub2/Cdc16 LysM domain catalytic) offer protection against oxidative stress and are widely implicated in neurological health and disease. How this family of proteins exerts their function, however, is poorly understood. We have recently found that the yeast TLDc protein, Oxr1p, inhibits the proton pumping vacuolar ATPase (V-ATPase) by inducing disassembly of the pump. While loss of TLDc protein function in mammals shares disease phenotypes with V-ATPase defects, whether TLDc proteins impact human V-ATPase activity directly is unclear. Here we examine the effects of five human TLDc proteins, TLDC2, NCOA7, OXR1, TBC1D24, and mEAK7 on the activity of the human V-ATPase. We find that while TLDC2, TBC1D24, and the TLDc domains of OXR1 and NCOA7 inhibit V-ATPase by inducing enzyme disassembly, mEAK7 activates the pump. The data thus shed new light both on mammalian TLDc protein function and V-ATPase regulation.

含有高度保守的 TLDc 结构域（Tre2/Bub2/Cdc16 LysM 催化结构域）的蛋白质可提供针对氧化应激的保护，并广泛涉及神经系统健康和疾病。然而，人们对这个蛋白质家族如何发挥其功能知之甚少。我们最近发现酵母 TLDc 蛋白 Oxr1p 通过诱导泵解体来抑制质子泵液泡 ATP 酶 (V-ATP 酶)。虽然哺乳动物中 TLDc 蛋白功能的丧失与 V-ATP 酶缺陷具有共同的疾病表型，但 TLDc 蛋白是否直接影响人类 V-ATP 酶活性尚不清楚。在这里，我们检查了五种人类 TLDc 蛋白 TLDC2、NCOA7、OXR1、TBC1D24 和 mEAK7 对人类 V-ATP 酶活性的影响。我们发现，虽然 TLDC2、TBC1D24 以及 OXR1 和 NCOA7 的 TLDc 结构域通过诱导酶解体来抑制 V-ATPase，但 mEAK7 却激活了泵。因此，这些数据为哺乳动物 TLDc 蛋白功能和 V-ATP 酶调节提供了新的线索。