학술논문
Structural basis underlying the synergism of NADase and SLO during group A Streptococcus infection
Document Type
article
Author
Tsai, Wei-Jiun; Lai, Yi-Hsin; Shi, Yong-An; Hammel, Michal; Duff, Anthony P; Whitten, Andrew E; Wilde, Karyn L; Wu, Chun-Ming; Knott, Robert; Jeng, U-Ser; Kang, Chia-Yu; Hsu, Chih-Yu; Wu, Jian-Li; Tsai, Pei-Jane; Chiang-Ni, Chuan; Wu, Jiunn-Jong; Lin, Yee-Shin; Liu, Ching-Chuan; Senda, Toshiya; Wang, Shuying
Source
Communications Biology. 6(1)
Subject
Language
Abstract
Group A Streptococcus (GAS) is a strict human pathogen possessing a unique pathogenic trait that utilizes the cooperative activity of NAD+-glycohydrolase (NADase) and Streptolysin O (SLO) to enhance its virulence. How NADase interacts with SLO to synergistically promote GAS cytotoxicity and intracellular survival is a long-standing question. Here, the structure and dynamic nature of the NADase/SLO complex are elucidated by X-ray crystallography and small-angle scattering, illustrating atomic details of the complex interface and functionally relevant conformations. Structure-guided studies reveal a salt-bridge interaction between NADase and SLO is important to cytotoxicity and resistance to phagocytic killing during GAS infection. Furthermore, the biological significance of the NADase/SLO complex in GAS virulence is demonstrated in a murine infection model. Overall, this work delivers the structure-functional relationship of the NADase/SLO complex and pinpoints the key interacting residues that are central to the coordinated actions of NADase and SLO in the pathogenesis of GAS infection.