Breast cancer-associated mutations in human ADAM12-L.

<p>(A) A diagram of human ADAM12-L. Six non-synonymous mutations identified in human breast cancers are indicated. S, signal peptide; P, prodomain; M, metalloproteinase domain; D, disintegrin domain; C, cysteine-rich domain; E, EGF-like domain; T, transmembrane region; Cyt, cytoplasmic tail. (B) Model of the extracellular domain of human ADAM12-L generated by the I-TASSER protein structure prediction tool (C-score <i>−</i>0.26, estimated TM accuracy of the model 0.68±0.12 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092536#pone.0092536-Roy2" target="_blank">[20]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092536#pone.0092536-Zhang1" target="_blank">[21]</a>). The metalloproteinase, disintegrin, cysteine-rich, and EGF-like domains are shown in purple, blue, yellow, and green, respectively. Positions of the five amino acids mutated in breast cancers (red spheres) and the side chain of the catalytic residue E351 (cyan sticks) are indicated. (C) Sequence alignment of the cysteine-rich and EGF-like domains of ADAM12 from different species. NCBI RefSeq numbers are: <i>Homo_sapiens</i>, NP_003465; <i>Mus_musculus</i>, NP_031426; <i>Rattus_norvegicus</i>, XP_001054670; <i>Bos_taurus</i>, NP_001001156, <i>Equus_caballus</i>, XP_001490097; <i>Gallus_gallus</i>, NP_001136322, and <i>Xenopus_tropicalis</i>, NP_001035103. (D) Sequence alignment of the cysteine-rich and EGF-like domains of human ADAM12 and the most closely related human ADAMs. NCBI RefSeq numbers are: ADAM19, XP_005266060, ADAM33, NP_079496.1, and ADAM15, NP_997080. In C and D, asterisks indicate three novel mutations in human ADAM12 found in breast tumors <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092536#pone.0092536-Shah1" target="_blank">[14]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092536#pone.0092536-Jiao1" target="_blank">[15]</a>. Clustal X color scheme was applied.