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. 2013 Oct 17;105(21):1617–1627. doi: 10.1093/jnci/djt249

Figure 4.

Figure 4.

Conservativeness of the amino acid sites of RASAL1 mutations. A) Multiple sequence alignment of the RAS GTPase-activating domain sequences derived from six human RasGAPs. The protein homologues were aligned by Constraint-based Multiple Alignment Tool of the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/tools/cobalt/). Sequence identity is shown in black boxes, dark gray boxes, and light gray boxes that represent different percentages of sequence identity, as indicated. The sequences that are substantially homologous among the RasGAP proteins are boxed and shown as blocks (39). The locations of RASAL1 mutations in the alignment sequence are indicated with arrows (for missense mutation) or stars (for nonsense mutation). Two missense mutations (R438C and R438H) occur at the same site and are thus indicated by one arrow. The locations of NF1 missense mutations in the alignment sequence are indicated with triangles. The NF1 mutation data was retrieved from databases HGMD (http://www.hgmd.cf.ac.uk) and COSMIC (http://www.sanger.ac.uk/genetics/CGP/cosmic/). B) Missense mutations in the similarity plot of RASAL1 homologues. The program Vector NTI (Invitrogen, Grand Island, NY) was used to generate the amino acid sequence similarity plot of RASAL1 homologues from 18 species, including Homo sapien (NP_004649.2), Pan troglodyte (XP_509394.2), Macaca mulatta (XP_002808039.1), Callithrix jacchus (XP_002753077.1), Bos taurus (XP_590469.5), Sus scrofa (XP_003132956.2), Equus caballus (XP_001915233.1), Ailuropoda melanoleuca (XP_002925340.1), Canis familiaris (XP_543403.2), Oryctolagus cuniculus (XP_002719824.1), Rattus norvegicus (NP_001101805.1), Mus musculus (NP_038860.2), Monodelphis domestica (XP_001378640.1), Meleagris gallopavo (XP_003211173), Tetraodon nigroviridis (CAF93132), Anolis carolinensis (XP_003226069.1), Saccoglossus kowalevskii (XP_002734139.1), and Xenopus tropicalis (NP_001008049.1). A sliding window of five amino acids was chosen. The x-axis represents coordinates on the amino acids and the y-axis shows similarity scores, with score 1 representing 100% sequence identity. The three dashed lines represent similarity scores of 1, 0.8, and 0.6, respectively. The RASAL1 missense mutations identified in this study are marked with red lines at the corresponding locations. All of the mutations are located in regions with similarity scores greater than 0.8.