Sequence analysis identifies a Ras-associating (RA)-like domain in the N-termini of band 4.1/JEF domains and in the Grb7/10/14 adapter family

RA (RalGEF/AF6 or Ras-associating) domains are found in a wide variety of p roteins, several of which are known to be Ras-GTP effecters. The three dime nsional structure of the BA domain has been experimentally determined in Ra l-guanine nucleotide exchange factor (Ral-GEF) and found to be similar to t hat of the Ras-binding domain of c-Raf1, in spite of a very low level of se quence identity. Using various approaches of sequence analysis, including a utomatic procedures such as BLAST2, profilescan, and hidden Markov models ( HMM), as well as the bidimensional hydrophobic cluster analysis (HCA), here we found that a region with a similar structure is also present at the N-t erminus of the band 4.1/JEF domain of KIAA0316 (a human cDNA open reading f rame) and H09G03.2 (a related protein sequence predicted from C. elegans ge nome cloning), as well as in a particular class of adapter proteins includi ng Grb7, Grb10, Grb14, MIG-10, and PRP48. Although the structural conservat ion of this motif does not necessarily imply a conservation of its ability to bind small GTPases of the Ras superfamily, several proteins with a band 4.1/JEF domain and adapters of the Grb7 group have close functional relatio nships with such small GTPases. Thus, our finding raises the intriguing pos sibility of a direct interaction between members of these two groups of pro teins and Ras-like GTP-binding proteins. (C) 1999 Academic Press.