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Institut de Biologie StructuraleGrenoble / France

Intrinsic disorder in cell signalling (Jensen)

Project leader: Malene Ringkjøbing Jensen

Bioinformatic studies have placed proteins implicated in cell signalling among those with the highest levels of intrinsic disorder in the human genome. Yet, from a structural biology perspective, our current knowledge about signal transmission is essentially limited to crystal structures of folded catalytic domains of kinases and phosphatases. We elucidate the role of intrinsic disorder in the mitogen-activated protein kinase (MAPK) cell signalling pathways. These pathways generally feature three sequentially acting protein kinases making up a signalling module. Intrinsically disordered proteins play crucial roles in ensuring signalling specificity by assembling the kinases into dynamic signalling complexes. This assembly occurs either through intrinsically disordered regulatory domains of the kinases themselves that contain interaction motifs selective for other kinases, or via a highly disordered scaffold protein that binds the three components of a signalling module. Currently, we have very little information about how these highly dynamic multi-enzyme complexes are assembled, how they are regulated by post-translational modifications and how they mediate specificity. Elucidating the molecular mechanisms underlying signalling specificity is particularly pertinent as deregulation of the MAPK pathways is strongly implicated in the development and progression of a number of human cancers and metabolic disorders. We aim at developing novel NMR methodologies and analytical tools for visualizing the assembly of scaffolding complexes, thereby providing the first atomic resolution description of the dynamic interaction network that underlies MAPK signalling specificity.

Selected publications:

Delaforge E, Kragelj J, Tengo L, Palencia A, Milles S, Bouvignies G, Salvi N, Blackledge M, Jensen MR.
Deciphering the Dynamic Interaction Profile of an Intrinsically Disordered Protein by NMR Exchange Spectroscopy
J Am Chem Soc. 2018, 140:1148-1158.

Kragelj J, Palencia A, Nanao MH, Maurin D, Bouvignies G, Blackledge M, Jensen MR.
Structure and dynamics of the MKK7-JNK signaling complex
Proc Natl Acad Sci U S A. 2015, 112:3409-14

Kragelj J, Ozenne V, Blackledge M, Jensen MR.
Conformational propensities of intrinsically disordered proteins from NMR chemical shifts
Chemphyschem. 2013, 14:3034-45