title: Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16).
abstract: 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 alpha/beta sandwich fold composed of two alpha helices and four antiparallel beta strands and has a characteristic turn named the TY-turn between alpha1 and alpha2. 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 beta sheet surface, which may be functionally important. The putative epitope (residues 58-77) for anti-MUC16 antibodies is located around the beta2 and beta3 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 beta2 and beta3.
authors.affiliation: RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Seizo
authors.initials: S
authors.lastname: Koshiba
authors.forename: Takashi
authors.initials: T
authors.lastname: Yabuki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Aoki
authors.forename: Emi
authors.initials: E
authors.lastname: Nunokawa
authors.forename: Eiko
authors.initials: E
authors.lastname: Seki
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Motoda
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hiroyasu
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Takaho
authors.initials: T
authors.lastname: Terada
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hayami
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ishizuka
authors.forename: Naoko
authors.initials: N
authors.lastname: Shinya
authors.forename: Ayako
authors.initials: A
authors.lastname: Tatsuguchi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirota
authors.forename: Yo
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Tani
authors.forename: Takahiro
authors.initials: T
authors.lastname: Arakawa
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Jun
authors.initials: J
authors.lastname: Kawai
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018394:CA-125 Antigen / Q000737:chemistry*; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
chemical_list: D018394:CA-125 Antigen; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; C451759:MUC16 protein, human; D008565:Membrane Proteins; C549756:NBR1 protein, human; C486326:Nbr1 protein, mouse; D011506:Proteins; D004247:DNA