NSF-BSF: Novel determinants of prokaryotic copper homeostasis

金属是所有生命形式必需的营养物质。特别是，铜在呼吸和抗氧化防御中起着重要作用。然而，过量的铜是有毒的，会损害细胞。因此，特定的蛋白质被用来结合铜并将其携带到不同的细胞位置。由于金属存在于三分之一的蛋白质中，因此研究它们的运输和递送具有重要意义，并影响对许多生物和环境过程的理解，包括全球元素循环。该项目的目标是研究细菌如何获得和分布铜。该项目将为各级的跨学科研究培训提供机会，并为当地社区提供指导和外联服务。此外，该项目将为美国和以色列的科学家提供一个密切合作的独特机会，从而扩大不同科学团体和开展研究方式的技能和经验。这种接触是在日益全球化的社会中培训科学家的一个重要组成部分。由于原核铜酶是胞质外的，大多数研究都是针对铜输入到周质进行酶装载或铜抗性机制，而很少关注控制胞质铜输入的可能性。然而，越来越多的证据表明，一些质周铜酶的装载可能需要进口到细胞质。假定的细胞质铜输入者包括CopD/YcnJ/YebZ跨膜蛋白家族成员。编码这些蛋白质的基因通常与编码质周铜结合蛋白（如CopCs和其他尚未表征的蛋白质）的基因相关。该项目将研究与胞质铜进口有关的周质和跨膜蛋白，主要关注大肠杆菌中发现的系统。该方法结合了遗传、计算、生物物理和结构方法，利用了美国和以色列合作实验室的互补专业知识。该研究将有助于阐明以前未被表征的铜结合蛋白的结构和功能，并将导致细菌铜稳态的新模型。这个美国/以色列合作项目由美国国家科学基金会和以色列两国科学基金会支持。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Metals are essential nutrients for all life forms. In particular, copper plays a role in respiration and antioxidant defense. However, too much copper is toxic and can damage cells. Therefore, specific proteins are used to bind copper and carry it to different cellular locations. Since metals are present in one third of all proteins, studying their transport and delivery is of fundamental importance and impacts understanding of many biological and environmental processes, including global element cycles. The goal of this project is to investigate how bacteria obtain and distribute copper. The project will provide opportunities for interdisciplinary research training at all levels as well as for mentoring and outreach in the local community. Moreover, the project will present a unique opportunity for scientists from the US and Israel to work closely together, leading to expanded skillsets and experiences with diverse scientific communities and ways of conducting research. Such exposure is an essential component of training scientists in an increasingly global society.Since prokaryotic copper enzymes are extracytoplasmic, most research has addressed either copper import to the periplasm for enzyme loading or mechanisms of copper resistance, with little focus on the possibility of controlled cytoplasmic copper import. Nevertheless, growing evidence suggests that import to the cytoplasm may be required for loading of some periplasmic copper enzymes. Putative cytoplasmic copper importers include members of the CopD/YcnJ/YebZ family of transmembrane proteins. Genes encoding these proteins are typically found associated with genes encoding periplasmic copper binding proteins, such as CopCs and other yet-to-be characterized proteins. This project will investigate both periplasmic and transmembrane proteins implicated in cyotplasmic copper import, focusing primarily on systems found in E. coli. The approach combines genetic, computational, biophysical, and structural methods that leverage the complementary expertises of the collaborating laboratories in the US and Israel. The research will result in elucidation of the structure and function of previously uncharacterized copper-binding proteins and will lead to new models of bacterial copper homeostasis.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.