Title:	Structural Biology of Transcriptional Regulators in Disease
DNr:	SNIC 2015/1-430
Project Type:	SNIC Medium Compute
Principal Investigator:	Maria Sunnerhagen <marsu@ifm.liu.se>
Affiliation:	Linköpings universitet
Duration:	2015-11-30 – 2016-12-01
Classification:	10601 10603 10602
Keywords:

Abstract

SUMMARY In my research group, we evaluate the structure and dynamics of transcriptional regulators and their interactions with DNA, with each other, with the translational machinery, with chromatin regulators, and with systems that govern protein stability such as ubiquitination and phosphorylation. Our main objectives of study are 1) the oncogene c-Myc, a highly attractive target for cancer therapeutics where we investigate both its internal structural and dynamic properties and its interactions with regulatory proteins, 2) the E3 ligase Ro52, which regulates interferone levels in cells and thereby affects gene expresion. In collaboration with prof Mikael Sigvardsson, HU/LiU, we are studying the transcriptional regulator Ebf1, which is essential for the differentiation of B-cells and thereby related to leukemia. Here, we combine the use of structural biology methods in my group with proteomics, bioinformatics and cellular biology, also in international collaboration with U Toronto. PROGRESS Our previous SNIC project has resulted in one publication (A), one submitted manuscript (B), and a manuscript in preparation ©: A. Pre-anchoring of Pin1 to unphosphorylated c-Myc in a dynamic complex affects c-Myc activity. Sara Helander, Meri Montecchio, Robert Pilstål, Yulong Su, Jacob Kuruvilla, Malin Johansson, Javed Mohammed, Madhanagopal Anandapadamanaban, Susana Cristobal, Patrik Lundström, Rosalie Sears, Björn Wallner & Maria Sunnerhagen (Structure 2015, in-press) B. Population shift disengages DNA binding in a multidrug resistance MexR mutant. Madhanagopal Anandapadamanaban, Robert Pilstål, Cecilia Andrésen, Jill Trewhella, Björn Wallner and Maria Sunnerhagen. (PNAS, submitted). Finally, we have during the previous project period resolved in atomic detail the structural mechanism of ubiquitination by TRIM21: C. Structure of a TRIM21 - UBE2E1 complex reveals the specificity of E2 and ubiquitin recognition by TRIM E3 RINGs. M Anandapadamanaban, N Kyriadikis, A Espinosa, A Round, J Trewhella, M Wahren-Herlenius, M Moche & M Sunnerhagen. (2015, manuscript in preparation). UPCOMING Our main task during the upcoming year will be continued characterisation of dynamic Myc and TRIM21 complexes by means of a combined use of NMR, biophysical and computational resources. We have preliminary data for a range of complexes which now await refinement. Furthermore, our joint translational approach to the proteomic study of Ebf1 interactions using structural, computational and biological methods requires significant computational power to address these complex data. Finally, I (Sunnerhagen) will as of Jan 2016 be the project leader of the PReSTO project in collaboration with MAXIV. In all these respects, NSC and Triolith is a critical asset for us to achieve our scientific and collaboratory goals.