A new structural paradigm in copper resistance in Streptococcus pneumoniae

作者：Fu Yue; Tsui Ho Ching Tiffany; Bruce Kevin E; Sham Lok To; Higgins Khadine A; Lisher John P; Kazmierczak Krystyna M; Maroney Michael J; Dann Charles E III; Winkler Malcolm E; Giedroc David P^*

来源：Nature Chemical Biology, 2013, 9(3): 177-183.

DOI：10.1038/NCHEMBIO.1168

Copper resistance has emerged as an important virulence determinant of microbial pathogens. In Streptococcus pneumoniae, copper resistance is mediated by the copper-responsive repressor CopY, CupA and the copper-effluxing P-18-type ATPase CopA. We show here that CupA is a previously uncharacterized cell membrane-anchored Cu-(I) chaperone and that a Cu-(I) binding-competent, membrane-localized CupA is obligatory for copper resistance. The crystal structures of the soluble domain of CupA and the N-terminal metal-binding domain (MBD) of CopA (CopA(MBD)) reveal isostructural cupredoxin-like folds that each harbor a binuclear Cu-(I) cluster unprecedented in bacterial copper trafficking. NMR studies reveal unidirectional Cu-(I) transfer from the low-affinity site on the soluble domain of CupA to the high-affinity site of CopA(MBD). However, copper binding by CopA(MBD) is not essential for cellular copper resistance, consistent with a primary role of CupA in cytoplasmic Cu-(I) sequestration and/or direct delivery to the transmembrane site of CopA for cellular efflux.

• 出版日期2013-3