Through structural biology, cell biology and biochemical reconstitutions we address the molecular details that govern signaling through the ubiquitin proteasome system. We combine this mechanistic understanding with large scale proteomics and computational methods, to understand the molecular principles of signaling through the ubiquitin system. We further seek to leverage our molecular understanding to propose and test new avenues of therapeutic intervention.
The Ubiquitin Proteasome System (UPS) is involved in virtually any cellular process and frequently implicated in human pathologies. Ubiquitin, through the action of a three-enzyme cascade (E1, E2 and E3), becomes attached to substrate proteins. The posttranslational modification with ubiquitin can serve a multitude of functions depending on the type and length of the ubiquitin chain attached to the substrate, including the control of protein abundance via proteasomal degradation. The human genome encodes for more than 600 E3 ligases, which confer specificity in the ubiquitin signaling cascade. While the process of ubiquitin transfer is well understood, the biological function and molecular mechanisms of the majority of ubiquitin ligases remain obscure.
We combine structural biology, cell biology and biochemical reconstitutions to address the molecular workings of these multi-component ubiquitin ligases. In particular, we are interested in protein complexes and pathways that contribute to the control of gene expression and are frequently associated with human disease and cancer. Intimate understanding of the structure allows us to dissect the complex mechanisms that underlie function and regulation of such molecules and to probe their biology in a cellular context. We seek to leverage our molecular understanding to propose and test new avenues of therapeutic intervention.
Another focus is on the use of small molecules for the targeted degradation of disease causing proteins, a new therapeutic modality now widely explored in academic research and the pharmaceutical industry. We helped establish many of the fundamental principles for how small molecules can redirect the activity of ubiquitin ligases for the controlled destruction of proteins. Using multi-disciplinary chemical biology (including X-ray crystallography, cryo-EM, proteomics, biochemistry and chemical synthesis), we define the mechanism of drugs such as thalidomide, lenalidomide, indisulam, etc. and leverage these findings to further refine approaches for the prospective development of small molecule degraders. We also develop computational methods to better understand and predict the molecular interations that comprise the activity of small molecule degraders.
Selected recent publications:
Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, Ebert BL, Fischer ES. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife 2018 Aug 1;7. pii: e38430. doi: 10.7554/eLife.38430.
Sievers QL, Gasser JA, Cowley GS, Fischer ES, Ebert BL. Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood. 2018 Sep 20;132(12):1293-1303. doi: 10.1182/blood-2018-01-821769. Epub 2018 Jul 24.
Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA, An J, Safaee N, Jedrychowski MP, Ponthier CM, Ishoey M, Zhang T, Mancias JD, Gray NS, Bradner JE, Fischer ES. Plasticity of inter-protein contacts confers selectivity in ligand induced protein degradation. Nature Chemical Biology (in press).
An J, Ponthier CM, Sack R, Seebacher J, Stadler MB, Donovan KA, Fischer ES. pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase. Nat Commun. 2017; 8:15398.
Cavadini, S, Fischer, ES, Bunker, R.D, Potenza, A, Gondichatnahalli, ML, Goldie, KN, Mohamed, WI, Faty, M, Petzold, G, Beckwith, REJ, Tichkule, R, Hassiepen, U, Abdulrahman, W., Pantelic, R.S., Matsumoto, S., Sugasawa, K., Stahlberg, H, Thomä, NH., Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature. 2016; 531(7596):598-603.
Petzoid G, Fischer ES, Thomä, NH. Structural basis of lenalidomide-induced CKla degradation by the CRL4CRBN ubiquitin ligase. Nature. 2016; 532(7597):127-30.
Fischer, ES, Böhm, K, Lydeard, JR, Yang, H, Stadler, MB, Cavadini, S, Nagel, J, Acker, V, Tichkule, R, Forrester, WC, Schirle, M, Hassiepen, U, Ottl, J, Hild, M, Beckwidth, REJ, Harper, JW, Jenkins, JL, Thomä, NH. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 2014 vol. 512 (7512) pp. 49-53.