M. Madan Babu

Discovering functional regions within disordered regions of G protein coupled receptors
Group Leader page

Signal transduction is a fundamental biological process that is required to maintain cellular homeostasis and to ensure coordinated cellular activity in all organisms. Membrane proteins at the cell surface serve as the communication interface between the cell's external and internal environments. One of the largest and most diverse membrane protein families is the GPCRs, which are encoded by more than 800 genes in the human genome.

GPCRs function by detecting a wide spectrum of extracellular signals, including photons, ions, small organic molecules and entire proteins. After ligand binding, GPCRs undergo conformational changes, causing the activation of complex cytosolic signalling networks, resulting in a cellular response. Altering the activities of GPCRs through drugs is already used in the treatment of numerous ailments including cardiac malfunction, asthma and migraines. Given the tremendous diversity of GPCRs, there remains enormous potential for the development of drugs to ameliorate neurological disorders, inflammatory diseases, cancer and metabolic imbalances.

Recent developments are providing unprecedented insights into the structure and function of several medically important GPCRs. However, a substantial portion of GPCRs does not adopt defined three-dimensional structures and remain unstructured. Thus a key aim of this project is to identify the functional segments within disordered regions of human GPCRs and understand how they contribute to receptor function.

To investigate this question, we will employ several complementary approaches involving large-scale data analysis and machine learning. Specifically, this project will require prior knowledge and experience in comparative genomics approaches, next generation sequencing data analysis, natural variation data, transcriptome analysis, network, structural and sequence analysis among others.

Understanding how disordered regions contribute to the functioning of GPCRs has the enormous potential to uncover novel aspects of receptor biology. Thus a keen interest in the biology of different GPCRs will be valuable. Ideal PhD candidates will have extensive programming knowledge, experience in computational biology, and will be passionate about proteins, specifically GPCRs.


References:

Flock, T., Hauser, A.S., Lund, N., Gloriam, D.E., Balaji, S. and Babu, M.M. (2017)
Selectivity determinants of GPCR-G-protein binding.
Nature. 545(7654):317-322.

Venkatakrishnan, A.J., Deupi, X., Lebon, G., Heydenreich, F.M., Flock, T., Miljus, T., Balaji, S., Bouvier, M., Veprintsev, D.B., Tate, C.G., Schertler, G.F. and Babu, M.M. (2016)
Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region.
Nature. 536(7617):484-7.

Flock, T., Ravarani, C.N.J., Sun. D., Venkatakrishnan, A.J., Kayikci, M., Tate, C.G., Veprintsev, D.B. and Babu, M.M. (2015)
Universal allosteric mechanism for Gα activation by GPCRs.
Nature. 524(7564):173-179.

Venkatakrishnan, A.J., Flock, T., Prado, D.E., Oates, M.E., Gough, J. and Babu, M.M.  (2014)
Structured and disordered facets of the GPCR fold.
Curr Opin Struct Biol. 27:129-37

Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C.G., Schertler, G.F. and Babu, M.M. (2013)
Molecular signatures of G-protein-coupled receptors.
Nature., 494(7436):185-94.

Babu, M.M. (2016)
The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease.
Biochem Soc Trans. 44(5):1185-1200.

van der Lee, R., Buljan, M., Lang, B., Weatheritt, R.J., Daughdrill, G.W., Dunker, A.K., Fuxreiter, M., Gough, J., Gsponer, J., Jones, D.T., Kim, P.M., Kriwacki, R.W., Oldfield, C.J., Pappu, R.V., Tompa, P., Uversky, V.N., Wright, P.E. and Babu, M.M. (2014)
Classification of intrinsically disordered regions and proteins.
Chem Rev. 114(13):6589-631.

Tompa, P., Davey, N.E., Gibson, T.J. and Babu, M.M. (2014)
A million peptide motifs for the molecular biologist.
Mol Cell. 55(2):161-9.

Buljan, M., Chalancon, G., Eustermann, S., Wagner, G.P., Fuxreiter, M., Bateman, A. and Babu, M.M. (2012)
Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks.
Mol Cell. 46(6):871-83.

Gsponer, J., Futschik, M., Teichmann, S.A. &Madan Babu, M. (2008)
Tight regulation of unstructured proteins: from transcript synthesis to protein degradation.
Science., 322(5906), 1365-8.