Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
文献类型：期刊论文
| 作者 | Tam, Kayan1; Schultz, Megan1; Reyes-Robles, Tamara1; Vanwalscappel, Benedicte1; Horton, Joshua1; Alonzo, Francis, III1; Wu, Beili2 ; Landau, Nathaniel R.1; Torres, Victor J.1
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| 刊名 | MBIO
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| 出版日期 | 2016-11 |
| 卷号 | 7期号:6 |
| ISSN号 | 2150-7511 |
| DOI | 10.1128/mBio.02024-16 |
| 文献子类 | Article |
| 英文摘要 | Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5. IMPORTANCE The bicomponent pore-forming toxins are thought to play a vital role in the success of Staphylococcus aureus as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV-1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions. |
| WOS关键词 | PANTON-VALENTINE LEUKOCIDIN ; CHEMOKINE RECEPTOR CCR5 ; 2ND EXTRACELLULAR LOOP ; NILE-VIRUS-INFECTION ; PORE-FORMING TOXINS ; HUMAN C5A RECEPTORS ; HUMAN NEUTROPHILS ; CRYSTAL-STRUCTURE ; ENTRY INHIBITOR ; HEMOLYSIN |
| 资助项目 | HHS|NIH| National Institute of Allergy and Infectious Diseases (NIAID)[AI007180] ; HHS|NIH| National Institute of Allergy and Infectious Diseases (NIAID)[AI112290] ; HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)[AI105129] ; HHS| NIH | National Institute of Allergy and Infectious Diseases (NIAID)[AI067059] ; HHS| NIH | National Institute of Allergy and Infectious Diseases (NIAID)[AI22390] ; HHS| NIH | National Institute of Allergy and Infectious Diseases (NIAID)[AI073237] |
| WOS研究方向 | Microbiology |
| 语种 | 英语 |
| 出版者 | AMER SOC MICROBIOLOGY |
| WOS记录号 | WOS:000392079500059 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275823]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Landau, Nathaniel R.; Torres, Victor J. |
| 作者单位 | 1.NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tam, Kayan,Schultz, Megan,Reyes-Robles, Tamara,et al. Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5[J]. MBIO,2016,7(6). |
| APA | Tam, Kayan.,Schultz, Megan.,Reyes-Robles, Tamara.,Vanwalscappel, Benedicte.,Horton, Joshua.,...&Torres, Victor J..(2016).Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5.MBIO,7(6). |
| MLA | Tam, Kayan,et al."Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5".MBIO 7.6(2016). |
入库方式： OAI收割
来源：上海药物研究所
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