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Hamburg, 1 December 2012

Unzipping melanocyte regulation

Structure of transcription factor MITF resolved


Structure of MITF in the presence of its specific DNA target.
Credit: EMBL/M. Wilmanns

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Scientists from EMBL Hamburg have resolved the structure of a transcription factor crucial in the development of melanoma. The data published today in the journal Genes and Development provide a rational basis for the treatment of important hereditary diseases and cancer by targeting MITF.

Microphthalmia associated transcription factor (MITF) functions as a master regulator in cells which produce skin pigments (melanocytes). MITF is essential for the development, survival and differentiation of these cells. It also plays crucial roles in other key cell types and mutations of the Mitf gene have been found across the animal kingdom with consequences varying from premature death to pigmentation and deafness syndromes, as seen in humans. Important recent evidence shows that MITF also has a crucial role in the development of the skin cancer melanoma.

Melanoma is a malignant tumour of the melanocytes and while it is not as common as other types of skin cancer, it can be fatal if not caught early and accounts for ca 75% of skin cancer related deaths. In today’s paper, scientists from EMBL Hamburg, together with colleagues from Iceland, characterised the DNA binding and dimerisation specificities of MITF by use of structural and functional analyses. The data show that MITF has some unusual and unexpected structural features when compared to similar transcription factors, which would explain its distinct role as a master transcription factor.

“The structure shows a very unusual 3 residue insertion in the leucine zipper register resulting in a kink in one of the zipper helices,” explains Vivian Pogenberg from EMBL Hamburg who carried out the research, “this insertion limits MITF’s ability to dimerise only with those transcription factors that also have this unusual insert”. DNA binding is also shown to be very specific and mutants show an increase in non-specific DNA binding, illustrating how important this delicate balance between specific and non-specific binding is for MITF’s role as a master regulator in the development, survival and differentiation of melanocytes.

“Ultimately the goal will be to fully understand how MITF functions to evaluate how it can be targeted for potential cancer treatments” says Matthias Wilmanns, group leader at EMBL Hamburg who led the research. “A key future challenge therefore will be to expand our studies to look at the complete protein and its ligands including functional cooperation across the protein before we can systematically target MITF for therapeutic approaches”.

The study was the result of a collaboration with Eirikur Steingrimsson from the Biomedical Center at the University of Iceland. The EMBL Hamburg team is very pleased to have been able to work with Steingrimsson on this project and hope that this will be the first of many projects together. “I think this shows just how productive it can be for institutes who have access to large state-of-the-art infrastructures to work with partners who have a lot of expertise in complementary approaches but themselves no direct access to large instruments. We both benefitted greatly from this collaboration and hope it will mark the first of many great ground breaking projects,” Matthias Wilmanns concludes.

Source article

Pogenberg, V., Ogmundsdóttir, M., Bergsteinsdóttir, K., Schepsky, A., Phung. B., Deineko, V., Milewski, M., Steingrímsson, E., & Wilmanns, M. Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF. Genes & Development, 1 December 2012