25 years of puzzling over protein folding

Tuesday, May 5th, 2015

With contributions from the Udgaonkar lab and Ipsita Herlekar.

The Protein Folding Lab at NCBS has turned 25. Jayant Udgaonkar's lab is one of NCBS's oldest laboratories. In 1990, Udgaonkar was the first scientist from outside TIFR to be recruited to the nascent NCBS. It would be two years before all the formal approvals for NCBS came through, but in the meantime Udgaonkar's lab started work on the mechanism of protein folding, which it continues even today. The group had its beginnings at TIFR Mumbai, before moving to Bangalore.

Now a senior professor at NCBS, Udgaonkar, along with his students, has made quite a few contributions, both significant and original, to protein folding research. They have been successful in showing that protein folding commences by a non-specific chain collapse reaction, and unfolding by selective loosening of the protein structure. Their research has also revealed the robustness of folding and unfolding reactions in utilizing multiple pathways whose use depends on the folding conditions, and the presence of chaperone proteins. Further, the research group has also demonstrated the malleability of the structures of folding intermediates, showing that they can be modulated by the presence of osmolytes or by other means, and that the heterogeneity of folding intermediates reduces in more stabilizing conditions. Udgaonkar's work has revealed the possibility that folding reactions can be gradual in nature, and tuning the energy landscape has been shown to effect a switch from gradual to all-or-none folding. They have elucidated the structural mechanism of misfolding by the prion protein in addition to delineating the mechanism of induction of fibril formation by tau, a protein implicated in Alzheimer's disease. Unlike most other labs working on protein folding, Udgaonkar's lab pursues an experimental strategy using many different probes to tease apart the heterogeneity of folding, unfolding and misfolding reactions. His laboratory has collaborated extensively with that of G. Krishnamoorthy of TIFR, in the application of time resolved fluorescence methods to protein folding. "Jayant started with simple experiments that did not involve any fancy techniques, but were based on unique questions that he pursued with great zest. He believes there is more than one way of looking at a problem. This sets him apart from the other scientists in his field." says, his colleague and friend, M.K. Mathew.

Udgaonkar's contributions to research in protein folding has won him many laurels and prestigious awards, both national and international. He is the recipient of the Biotechnology Career Fellowship (Rockefeller Foundation), Swarnajayanti Fellowship (DST), Golden Jubilee Biotechnology Fellowship (DBT) Senior Research Fellowship (Wellcome Trust), J.C. Bose National Fellowship (DST), the Bhatnagar Award and G.N. Ramachandran Gold Medal (CSIR) and the Distinguished Alumnus Award (IIT, Madras). He is a fellow of the Indian Academy of Sciences, the Indian National Science Academy and The World Academy of Sciences. "Jayant's work has furthered our understanding of how proteins fold, unfold and aggregate. A subset of his many important contributions include showing that hydrophobic collapse precedes secondary structure formation during folding, one of the first observations of an unfolding intermediate, the existence and characterization of dry molten globules preceding the transition state in protein unfolding and careful characterization of intermediates formed during the process of protein aggregation, amyloid and prion formation. I have greatly benefited from having him close by, as a friend and collaborator." Says one of his first associates R.Varadarajan, Professor at IISc.

In addition to his research, Udgaonkar along with M.K. Mathew has been teaching the physical biochemistry course, one of the first courses started in NCBS. For over twenty one years, it has remained one of the most rigorous courses which students take up in the first semester of their coursework. The amount of matter covered in the course is comprehensive, with the range of fundamental topics covered useful to students from all disciplines of science. "While many view teaching as the transfer of knowledge from the notebooks of the teachers to the notebooks of the students; Jayant ensured that you were in class at sharp 9 am and were ready to think about the problem versus just scribbling notes." says Aniruddha Panda, a graduate student at NCBS.

"Scientifically he has been a rock, setting a standard for others to meet. Like broad ties and narrow ties, fashions in science change. Over his 25 years in NCBS, Jayant showed steely contempt for the pursuit of trendiness, while at the same time establishing himself and his lab as pioneers and leading authorities in the field of protein folding. Now, the pendulum has swung back and the importance of protein folding has been discovered as fundamental to the understanding neurodegenerative disease." says Mani Ramaswamy. These sentiments are not just limited to Udgaonkar's colleagues but are echoed by his students as well. They describe him as a mentor par excellence who encourages them to solve problems on their own. This support has given them the strength for a life outside the lab. Scribbled on the lab whiteboard for many years is the lab motto: Bolne se kya faida, kar ke dikhao.

Alongside pursuing high quality research, Udgaonkar served for over ten years as the first Dean of NCBS, helping to run the growing institute smoothly and efficiently.

"Jayant's tenure as Dean saw the building of the physical and cultural foundations of NCBS. Taming the beasts of bureaucracy, bringing in beauty as a core-value in our surroundings, insisting on quality course-work and rigour in training and in general holding us all to the highest standards are Jayant's trademarks. Having to convince Jayant meant to keep all your facts and the best arguments at hand. I had to rehearse my pitch for weeks before daring to face him. NCBS owes Jayant much. There are two assays a geneticist uses. By the deletion test, there is no doubt that if we were to imagine NCBS without Jayant, we would be a very different place. By the gain-of-function test, it is clear that a young person with Jayant's talents would do wonders in each of the many new institutions in country. I am sure many from NCBS would be these instruments of gain-of-Jayant-like-function and will be already transforming new environments. Happy 25th birthday and all best for another 25 at least." K. VijayRaghavan, former Director of NCBS.

In the words of Satyajit Mayor, current Director of NCBS "Jayant is not only an outstanding scientist, outstanding citizen and a shaper of institutions, he is a warm and deeply caring individual. Watching Vijay and Jayant run NCBS was like watching a see-saw at work, a intricate balancing act of sorts. Vijay, with his exuberant style, an inability to say no to anything, closely counterposed with Jayant's pragmatic realism. I always remember that to get something done at NCBS when Jayant was Dean, getting Vijay to agree was easy, Jayant was the immovable sphinx. But even he is susceptible; there was nothing that could not be obtained from Jayant if sufficient amounts of his favourite Alphonso mangoes were dangled as inducements! His 25 years at NCBS have been our founding bedrock, and continues to be transformative for science not only at NCBS but in India at large, mainly by the dint of his application, persistence and inventiveness as a scientist. I hope he will continue his great work for times to come."

On the behalf of everyone at NCBS, we wish Udgaonkar and his team all the very best on their future endeavours.


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