A chemical approach to the structural and biophysical study of the Id proteins and to the modulation of their biological functions

• Applicant: Professorin Dr. Chiara Cabrele
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2003 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5396788

The Id proteins regulate the cell cycle upon protein-protein interaction with transcription factors of the basic helix-loop-helix (bHLH) family, which leads to inhibition of DNA binding and, consequently, of cell differentiation. Also, Id2 binds to the retinoblastoma protein (pRb), a tumor suppressor protein, and antagonizes the pRb-induced cell-cycle arrest. Deregulated Id protein expression has been related to several human tumors (e.g., neuroblastoma, pancreatic, breast and endometrial cancers) and to tumor angiogenesis. Therefore, the Id proteins are potential targets for inhibiting tumor growth. The aim of this project will be the structural and biophysical characterization of the HLH dimerization domain of the Id proteins, with the long-term goal to design and develop Id inhibitors with anti-tumor activity. For this purpose, differently long polypeptides based on the natural HLH motifs of the Id proteins and analogs containing structure-inducing elements, fluorescent or spin labels will be prepared by peptide synthesis by the classical methods and/or by chemical and expressed protein ligation. The insight gained into the conformational and chemical properties of the dimerization interface will help to design small peptide-based as well as non-peptide-based compounds able to recognize the HLH domain of the Id proteins. Molecular recognition events will be investigated by spectroscopic, fluorimetric and calorimetric experiments, and subsequently the synthetic molecules will be tested in vitro for inhibition of tumor growth and angiogenesis.

• DFG Programme: Independent Junior Research Groups