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Mycobacterium tuberculosis CarD, an essential global transcriptional regulator forms amyloid-like fibrils

DOI: 10.1038/s41598-018-28290-4 DOI Help

Authors: Gundeep Kaur (Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH); Wellcome Trust Centre for Human Genetics, University of Oxford) , Soni Kaundal (Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH)) , Srajan Kapoor (Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH)) , Jonathan M. Grimes (Wellcome Trust Centre for Human Genetics, University of Oxford; Diamond Light Source) , Juha T. Huiskonen (Wellcome Trust Centre for Human Genetics, University of Oxford; Helsinki Institute of Life Science (HiLIFE)) , Krishan Gopal Thakur (Council of Scientific and Industrial Research-Institute of Microbial Technology (CSIR-IMTECH))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 8

State: Published (Approved)
Published: July 2018
Diamond Proposal Number(s): 10627

Open Access Open Access

Abstract: CarD is an essential global transcription regulator from Mycobacterium tuberculosis (Mtb) that binds RNA polymerase and activates transcription by stabilizing the transcription initiation complex. Available crystal structures have captured two distinct, monomeric and domain-swapped homodimeric, oligomeric states of CarD. However, the actual oligomeric state of CarD in solution and its biological relevance has remained unclear. Here, we confirm the presence of the homodimeric state of CarD in solution by using synchrotron-based small-angle X-ray scattering. Furthermore, by using biochemical and biophysical experiments, in addition to mass-spectrometry, transmission electron microscopy, and confocal imaging, we show that CarD is the first soluble cytosolic protein in Mtb which displays the tendency to form amyloid-like fibrils both in vitro as well as in vivo. We demonstrate that the deletion of the fourteen N-terminal residues involved in domain-swapping hampers amyloid formation, thus, suggesting that domain-swapping is crucial in amyloidogenesis. The discovery of the amyloidogenic property of an essential cytosolic global transcription regulator, CarD, in a pathogenic bacteria will further open up new frontiers in research.

Journal Keywords: SAXS; Transcription factors

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS

Documents:
s41598-018-28290-4.pdf