Solution Structure of the SEA Domain from the Murine Homologue of Ovarian Cancer Antigen CA125 (MUC16)

Takeshi Maeda, Makoto Inoue, Seizo Koshiba, Takashi Yabuki, Masaaki Aoki, Emi Nunokawa, Eiko Seki, Takayoshi Matsuda, Yoko Motoda, Atsuo Kobayashi, Fumiko Hiroyasu, Mikako Shirouzu, Takaho Terada, Nobuhiro Hayami, Yoshiko Ishizuka, Naoko Shinya, Ayako Tatsuguchi, Mayumi Yoshida, Hiroshi Hirota, Yo MatsuoKazutoshi Tani, Takahiro Arakawa, Piero Carninci, Jun Kawai, Yoshihide Hayashizaki, Takanori Kigawa, Shigeyuki Yokoyama

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74 Citations (Scopus)


Human CA125, encoded by the MUC16 gene, is an ovarian cancer antigen widely used for a serum assay. Its extracellular region consists of tandem repeats of SEA domains. In this study we determined the three-dimensional structure of the SEA domain from the murine MUC16 homologue using multidimensional NMR spectroscopy. The domain forms a unique α/β sandwich fold composed of two α helices and four antiparallel β strands and has a characteristic turn named the TY-turn between α1 and α2. The internal mobility of the main chain is low throughout the domain. The residues that form the hydrophobic core and the TY-turn are fully conserved in all SEA domain sequences, indicating that the fold is common in the family. Interestingly, no other residues are conserved throughout the family. Thus, the sequence alignment of the SEA domain family was refined on the basis of the three-dimensional structure, which allowed us to classify the SEA domains into several subfamilies. The residues on the surface differ between these subfamilies, suggesting that each subfamily has a different function. In the MUC16 SEA domains, the conserved surface residues, Asn-10, Thr-12, Arg-63, Asp-75, Asp-112, Ser-115, and Phe-117, are clustered on the β sheet surface, which may be functionally important. The putative epitope (residues 58-77) for anti-MUC16 antibodies is located around the β2 and β3 strands. On the other hand the tissue tumor marker MUC1 has a SEA domain belonging to another subfamily, and its GSVVV motif for proteolytic cleavage is located in the short loop connecting β2 and β3.

Original languageEnglish
Pages (from-to)13174-13182
Number of pages9
JournalJournal of Biological Chemistry
Issue number13
Publication statusPublished - 2004 Mar 26


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