Abstract
The oncogenic transcription factor Myc is one of the most interesting members of the basic-helix-loop-helix-zipper (bHLHZip) protein family. Deregulation of Myc via gene amplification, chromosomal translocation or other mechanisms lead to tumorigenesis including Burkitt lymphoma, multiple myeloma, and many other malignancies. The oncogene myc is a highly potent transforming gene and capable to transform various cell types in vivo and in vitro. Its oncogenic activity initialized by deregulated expression leads to a shift of the equilibrium in the Myc/Max/Mad network towards Myc/Max complexes. The Myc/Max heterodimerization is a prerequisite for transcriptional functionality of Myc. Primarily, we are focusing on the apo-state of the C-terminal domain of v-Myc, the retroviral homolog of human c-Myc. Based on multi-dimensional NMR measurements v-Myc appears to be neither a fully structured nor a completely unstructured protein. The bHLHZip domain of v-Myc does not exist as a random coil but exhibits partially pre-formed α-helical regions in its apo-state. In order to elucidate the structural propensities of Myc in more detail, the backbone and side-chain assignments obtained here for apo-Myc are a crucial prerequisite for further NMR measurements.
Highlights
The oncogenic transcription factor Myc is one of the most interesting members of the basic-helix-loophelix-zipper protein family
Deregulation of Myc via gene amplification, chromosomal translocation or other mechanisms lead to tumorigenesis including Burkitt lymphoma, multiple myeloma, and many other malignancies
Its oncogenic activity initialized by deregulated expression leads to a shift of the equilibrium in the Myc/Max/Mad network towards Myc/Max complexes
Summary
The v-myc oncogene encoding the v-Myc protein is the transforming principle of avian Myelocytomatosis virus MC29 (Bister and Jansen 1986), an acute leukemia virus isolated from a chicken tumor (Ivanov et al 1964). The partially folded monomeric Myc showed dynamic features such as helical fraying and a directed flexibility in the loop region. Myc is another example for the growing evidence that binding interactions with intrinsically disordered proteins (IDP) largely proceed via conformational selection from a significantly narrowed conformation ensemble. Severe spectral overlaps make complete signal assignment a challenging task in IDPs. Lavigne et al provided 1998 a solution structure of N-terminal disulfide-linked versions of the c-Myc-Max heterodimeric Leucine Zipper solved by 2D H-NMR. We provide a complete signal assignment, backbone and side-chain, for the bHLHZip domain of apo (monomeric) v-Myc, using a set of high-dimensional triple resonance NMR experiments. Our data will be crucial for the characterization of Myc’s apo-state, and a valuable source of information for the analysis of amino-acid side chains in IDPs
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