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1. Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding.

Author

Joseph A Newman, Christopher D O Cooper, Anette K Roos, Hazel Aitkenhead, Udo C T Oppermann, Hearn J Cho, Roman Osman, and Opher Gileadi

Subjects
Medicine, Science
Abstract

The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE-A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is predominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders.

Published
2016
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2. Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding

Author

Christopher D.O. Cooper, Roman Osman, Hearn J. Cho, J.A. Newman, Anette K. Roos, Hazel Aitkenhead, Opher Gileadi, and Udo Oppermann

Subjects
0301 basic medicine, Models, Molecular, lcsh:Medicine, Plasma protein binding, Crystallography, X-Ray, Biochemistry, Protein structure, Ubiquitin, Materials Physics, Macromolecular Structure Analysis, Chemical Precipitation, lcsh:Science, Peptide sequence, Multidisciplinary, Crystallography, Molecular Structure, Effector, Physics, Chemical Reactions, Condensed Matter Physics, 3. Good health, Cell biology, Neoplasm Proteins, Chemistry, Physical Sciences, Crystal Structure, Crystallization, Sedimentation, Sequence Analysis, Protein Binding, Research Article, Protein Structure, endocrine system, Protein family, Allosteric regulation, Molecular Sequence Data, Materials Science, Biology, Research and Analysis Methods, QH301, 03 medical and health sciences, Allosteric Regulation, Antigens, Neoplasm, Sequence Motif Analysis, Electron Density, Humans, Solid State Physics, Amino Acid Sequence, Protein Structure, Quaternary, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, neoplasms, Melanoma-associated antigen, Cancer och onkologi, Chemical Physics, lcsh:R, Biology and Life Sciences, Proteins, Peptide Fragments, Protein Structure, Tertiary, 030104 developmental biology, Cancer and Oncology, biology.protein, lcsh:Q, Sequence Alignment
Abstract

The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE- A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is pre- dominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders.

Published
2016

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