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A novel function for a protein in Mycobacteria

Tuberculosis still remains one of the most deadly diseases affecting humans, and is responsible for over 2 million deaths all over the world. The causative agent of this disease is a bacterium, Mycobacterium tuberculosis, which persists in more than a billion individuals. The ability of the bacterium to survive in the human body for long periods of time, in a “latent” phase, without evoking any symptom of the disease makes it a very successful invader. In most people, the infection is suppressed by a healthy immune system. However, the bacteria are not removed completely from the body. Once infected, people are always at a risk: the pathogen could get re-activated, making the immune system deteriorate and causing tuberculosis to develop. Around one-third of the world’s population harbours viable bacteria in the latent phase of infection.

Studies have shown that bacteria persist in the human body in a non-growing state in structures known as “granulomas”. Within a granuloma, the pathogen encounters an oxygen-deprived environment that triggers the non-replicative, persistent latent phase. Under such conditions, Mycobacterium tuberculosis expresses certain proteins known as Universal Stress Proteins (USP) which may help the pathogen adapt to stress conditions induced by low oxygen levels, thereby enabling its survival.

Another important molecule synthesized by the bacteria, which has been implicated in disease establishment is Cyclic Adenosine Monophosphate (cAMP). These molecules act as second messengers in various signalling pathways present in many living organisms.

In this study, researchers from the Indian Institute of Science and the University of Bayreuth, Germany have identified a novel cAMP binding protein, using biochemical approaches. This protein is a Universal Stress Protein known as USP Rv1636. It has been shown to bind cAMP with high affinity and binds to Adenosine Triphosphate (ATP, the energy currency of the cell) with lower affinity.

Another species of Mycobacterium that the researchers have used is Mycobacterium smegmatis. This has been used as model organism for most Mycobacterial research owing to its relatively faster growth. Similar to Rv1636 which is present in Mycobacterium tuberculosis, M. smegmatis contains MSMEG_3811. Thus, orthologs exist in both fast as well as slow growing members of the genus Mycobacterium. The scientists have also characterised the structure of this protein bound to cAMP, which revealed a cAMP-binding module different from those described till date. This indicates the diverse functions undertaken by members of the Universal Stress Protein family. Another striking function of these USPs, as reported by the researchers, is their ability to act as sinks for second messengers like cAMP. The researchers suggest that these protiens function as banks where cAMP is released based on the bacterium’s requirements.

The study has been published in the prestigious Journal of Biological Chemistry in the March issue and can be accessed from the journal for further reading.

About the authors

The study is a collaborative one between researchers in two institutions in two countries. Sandhya S. Visweswariah is a Professor at the Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore. Arka Banerjee is a PhD student in her laboratory. Jayashree Gopalakrishnapai is currently at the Amrita School of Biotechnology, Kollum, India.

Clemens Steegborn is with the Department of Biochemistry, University of Bayreuth, Germany. Ramona S. Adolph, Christiane Emmerich and Silke Kleinboelting are from the same institution.

Contact: Sandhya S. Visweswariah

E mail:; Tel: +91 80 22932542/2360999

The paper appeared in The Journal of Biological Chemistry on 23rd March 2015.