In order to adapt to the changing environment, bacteria must quickly transform extracellular information into appropriate intracellular reactions. Two component system (TCS) is the main signal transduction protein in prokaryotic cells to transform environmental stimuli into cellular responses.
Hptrsa is a newly discovered TCS, which is composed of G6P related sensor protein (HptA), transmembrane histidine kinase (HptS) and cytoplasmic effector (HptR).
Recently, a team led by Prof. TAO Yuyong from the School of Life Sciences, University of Science and Technology of China (USTC) of CAS, in cooperation with National Laboratory for Physics Sciences at the Microspace, revealed the mechanism of extracellular G6P signal transduction through Staphylococcus aureus HptRSA sensor complex, integrating a comprehensive application of biochemical and structural biology research methods.
HptRSA mediates glucose-6-phosphate (G6P) uptake and supports the growth and proliferation of Staphylococcus aureus in different host cells. However, the molecular mechanism of sensing G6P signal and triggering downstream reaction by HptRSA sensor complex has always been a mystery.
By analyzing the HptA structures in the substrate free state and G6P binding state respectively, the group found that G6P could bind to the gap between two HptA proteins and cause the two HptA proteins to close to each other.
The complex structure of HptA protein and HptSp shows that HptA can interact with HptS through constitutive interface and another switchable interface: when G6P is not bound, HptA and HptSp are bound far away from the membrane and cause two HptSps to be arranged in parallel; when HptA binds to G6P, the junction of HptA and HptSp is parallel to each other Switching to the side close to the membrane caused the rotation of HptSp, and the C-terminal of two HptSps approached each other, which led to extracellular signal transduction into the cell.
Possible activation mechanism of HptA-HptS signal transduction system. (Image by WANG Mingxing et al.)
On the basis of the above structural discovery, researchers combined biochemical and growth analysis of HptA and HptS mutants, and proposed the G6P HptRSA signal transduction mechanism mediated by interface switch.
These results provide important clues for the nutritional sensing mechanism of bacteria, and expand the understanding of TCS activation mode for external signal transmission.
(Written by WENG Jingwen, edited by LI Xiaoxi, USTC News Center)
