Max: A Helix-Loop-Helix Zipper Protein That Forms a Sequence-Specific DNA-Binding Complex with Myc

TLDR

Myc proto‑oncogenes drive cell proliferation and differentiation, yet their molecular mechanism is unclear, and their C‑terminal bHLH‑Zip domain is predicted to mediate DNA binding and protein interactions. Using the c‑Myc bHLH‑Zip domain to screen a cDNA library, the authors isolated Max, a bHLH‑Zip protein that specifically associates with Myc family members. Max forms a heterodimer with c‑Myc, N‑Myc, and L‑Myc through their HLH‑Zip domains, and this complex binds DNA in a sequence‑specific manner that requires both the dimerization domain and the c‑Myc basic region, suggesting that Myc proteins act as a restricted set of eukaryotic transcription factors.

Abstract

The myc protooncogene family has been implicated in cell proliferation, differentiation, and neoplasia, but its mechanism of function at the molecular level is unknown. The carboxyl terminus of Myc family proteins contains a basic region helix-loop-helix leucine zipper motif (bHLH-Zip), which has DNA-binding activity and has been predicted to mediate protein-protein interactions. The bHLH-Zip region of c-Myc was used to screen a complementary DNA (cDNA) expression library, and a bHLH-Zip protein, termed Max, was identified. Max specifically associated with c-Myc, N-Myc, and L-Myc proteins, but not with a number of other bHLH, bZip, or bHLH-Zip proteins. The interaction between Max and c-Myc was dependent on the integrity of the c-Myc HLH-Zip domain, but not on the basic region or other sequences outside the domain. Furthermore, the Myc-Max complex bound to DNA in a sequence-specific manner under conditions where neither Max nor Myc exhibited appreciable binding. The DNA-binding activity of the complex was dependent on both the dimerization domain and the basic region of c-Myc. These results suggest that Myc family proteins undergo a restricted set of interactions in the cell and may belong to the more general class of eukaryotic DNA-binding transcription factors.