Chen Tai-Yen, Wen Meng-Hsuan, Chen Huanhuan, Yan Guangjie, Zhang Yuteng, Chen Wenkai, Dokholyan Martin, Wang Jian, Dokholyan Nikolay
University of Houston.
Penn State College of Medicine.
Res Sq. 2024 Dec 9:rs.3.rs-5456520. doi: 10.21203/rs.3.rs-5456520/v1.
Copper is an essential element involved in various biochemical processes, such as mitochondrial energy production and antioxidant defense, but improper regulation can lead to cellular toxicity and disease. Copper Transporter 1 (CTR1) plays a key role in copper uptake and maintaining cellular copper homeostasis. Although CTR1 endocytosis was previously thought to reduce copper uptake when levels are high, it was unclear how rapid regulation is achieved. Using single-molecule localization microscopy and single-molecule neighbor density assays, we discovered that excess copper induces monomerization of the wild-type trimeric CTR1 prior to endocytosis, a response blocked in the endocytosis-deficient CTR1 (M150L) mutant. This monomerization rapidly halts copper uptake and prevents copper overload. These findings reveal changes in protein oligomerization as a new paradigm of metal transport regulation, linking CTR1's structural changes to its endocytosis and copper homeostasis.
铜是一种参与多种生物化学过程的必需元素，如线粒体能量产生和抗氧化防御，但调节不当会导致细胞毒性和疾病。铜转运蛋白1（CTR1）在铜摄取和维持细胞铜稳态中起关键作用。虽然以前认为CTR1内吞作用在铜水平高时会减少铜摄取，但尚不清楚如何实现快速调节。使用单分子定位显微镜和单分子邻域密度测定法，我们发现过量铜在内吞作用之前诱导野生型三聚体CTR1单体化，这种反应在缺乏内吞作用的CTR1（M150L）突变体中被阻断。这种单体化迅速停止铜摄取并防止铜过载。这些发现揭示了蛋白质寡聚化的变化作为金属转运调节的新范式，将CTR1的结构变化与其内吞作用和铜稳态联系起来。
