Role of PemI in the Staphylococcus aureus PemIK toxin–antitoxin complex: PemI controls PemK by acting as a PemK loop mimic

Author:

Kim Do-Hee123ORCID,Kang Sung-Min4ORCID,Baek Sung-Min3,Yoon Hye-Jin5,Jang Dong Man6,Kim Hyoun Sook6,Lee Sang Jae7ORCID,Lee Bong-Jin3ORCID

Affiliation:

1. Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea

2. Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Republic of Korea

3. The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

4. College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea

5. Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea

6. Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea

7. PAL-XFEL, Pohang Accelerator Laboratory, POSTECH, Pohang, Gyeongbuk 37673, Republic of Korea

Abstract

Abstract Staphylococcus aureus is a notorious and globally distributed pathogenic bacterium. New strategies to develop novel antibiotics based on intrinsic bacterial toxin–antitoxin (TA) systems have been recently reported. Because TA systems are present only in bacteria and not in humans, these distinctive systems are attractive targets for developing antibiotics with new modes of action. S. aureus PemIK is a type II TA system, comprising the toxin protein PemK and the labile antitoxin protein PemI. Here, we determined the crystal structures of both PemK and the PemIK complex, in which PemK is neutralized by PemI. Our biochemical approaches, including fluorescence quenching and polarization assays, identified Glu20, Arg25, Thr48, Thr49, and Arg84 of PemK as being important for RNase function. Our study indicates that the active site and RNA-binding residues of PemK are covered by PemI, leading to unique conformational changes in PemK accompanied by repositioning of the loop between β1 and β2. These changes can interfere with RNA binding by PemK. Overall, PemK adopts particular open and closed forms for precise neutralization by PemI. This structural and functional information on PemIK will contribute to the discovery and development of novel antibiotics in the form of peptides or small molecules inhibiting direct binding between PemI and PemK.

Funder

National Research Foundation of Korea

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference62 articles.

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