Crystal structure of cytomegalovirus IE1 protein reveals targeting of TRIM family member PML via coiled-coil interactions

Journal article

Publication Details

Author(s): Scherer M, Klingl S, Sevvana M, Otto V, Schilling EM, Stump J, Müller R, Reuter N, Sticht H, Muller Y, Stamminger T
Journal: Plos Pathogens
Publisher: Public Library of Science
Publication year: 2014
Volume: 10
Journal issue: 11
Pages range: e1004512
ISSN: 1553-7366
eISSN: 1553-7374


PML nuclear bodies (PML-NBs) are enigmatic structures of the cell nucleus that act as key mediators of intrinsic immunity against viral pathogens. PML itself is a member of the E3-ligase TRIM family of proteins that regulates a variety of innate immune signaling pathways. Consequently, viruses have evolved effector proteins to modify PML-NBs; however, little is known concerning structure-function relationships of viral antagonists. The herpesvirus human cytomegalovirus (HCMV) expresses the abundant immediate-early protein IE1 that colocalizes with PML-NBs and induces their dispersal, which correlates with the antagonization of NB-mediated intrinsic immunity. Here, we delineate the molecular basis for this antagonization by presenting the first crystal structure for the evolutionary conserved primate cytomegalovirus IE1 proteins. We show that IE1 consists of a globular core (IE1CORE) flanked by intrinsically disordered regions. The 2.3 Å crystal structure of IE1CORE displays an all ?-helical, femur-shaped fold, which lacks overall fold similarity with known protein structures, but shares secondary structure features recently observed in the coiled-coil domain of TRIM proteins. Yeast two-hybrid and coimmunoprecipitation experiments demonstrate that IE1CORE binds efficiently to the TRIM family member PML, and is able to induce PML deSUMOylation. Intriguingly, this results in the release of NB-associated proteins into the nucleoplasm, but not of PML itself. Importantly, we show that PML deSUMOylation by IE1CORE is sufficient to antagonize PML-NB-instituted intrinsic immunity. Moreover, co-immunoprecipitation experiments demonstrate that IE1CORE binds via the coiled-coil domain to PML and also interacts with TRIM5? We propose that IE1CORE sequesters PML and possibly other TRIM family members via structural mimicry using an extended binding surface formed by the coiled-coil region. This mode of interaction might render the antagonizing activity less susceptible to mutational escape.

FAU Authors / FAU Editors

Klingl, Stefan Dr.
Lehrstuhl für Biotechnik (Proteinstruktur und -design)
Muller, Yves Prof. Dr.
Lehrstuhl für Biotechnik (Proteinstruktur und -design)
Otto, Victoria
Professur für Virologie
Scherer, Myriam
Professur für Virologie
Schilling, Eva-Maria
Professur für Virologie
Sevvana, Madhumati Dr.
Lehrstuhl für Biotechnik (Proteinstruktur und -design)
Stamminger, Thomas Prof. Dr.
Professur für Virologie
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik
Stump, Joachim
Professur für Bioinformatik

How to cite

Scherer, M., Klingl, S., Sevvana, M., Otto, V., Schilling, E.-M., Stump, J.,... Stamminger, T. (2014). Crystal structure of cytomegalovirus IE1 protein reveals targeting of TRIM family member PML via coiled-coil interactions. Plos Pathogens, 10(11), e1004512.

Scherer, Myriam, et al. "Crystal structure of cytomegalovirus IE1 protein reveals targeting of TRIM family member PML via coiled-coil interactions." Plos Pathogens 10.11 (2014): e1004512.


Last updated on 2018-30-05 at 08:01