Crystal structure of human SH3BGRL protein: the first structure of the human SH3BGR family representing a novel class of thioredoxin fold proteins.

Introduction. The humanSH3BGRL (h-SH3BGRL) gene is a member of the human SH3BGR family. The human SH3BGR (SH3 binding glutamic acid-rich) gene was cloned and characterized in 1997 in an effort to identify new genes located to chromosome 21. After the characterization of SH3BGR, three novel human genes, h-SH3BGRL, h-SH3BGRL2, and h-SH3BGRL3, were identified, showing a high homology to the N-terminal region of the h-SH3BGR protein. They are therefore believed to be a new family of human gene, the h-SH3BGR gene family. The h-SH3BGRL gene located to chromosome Xq13.3 encodes for a small protein of 114 amino acids, which is apparently widely expressed in many tissues including liver and blood. The h-SH3BGRLprotein features a prolinerich sequence (PLPPQIF), which contains both the SH3 binding (PXXP) and the Homer EVH1 binding (PPXXF) motif. This proline-rich region is highly conserved in h-SH3BGR family and was expected to be functionally important. Although it is known that the SH3BGRL gene is missing in a mentally retarded male patient, the exact functional role of h-SH3BGRL is still needed to be defined. Here we report the crystal structure of h-SH3BGRL protein determined by the SIRAS method. The structure indicates that SH3BGRL can not bind to the SH3 or Homer EVH1 domain as previously expected due to our finding that the binding motif (PLPPQIF) is buried in the tertiary structure. As the first structure of the human SH3BGR protein family, the tertiary structure of h-SH3BGRL shows a typical thioredoxin fold at the Nterminal part and a helix-loop-helix motif at the Cterminal lobe. Sequence and structure comparisons show that h-SH3BGRL belongs to the thioredoxin fold protein family but it is distinct from all five classes of the thioredoxin fold proteins identified thus far. According to the unique structural and functional characterizations, h-SH3BGRL represents a novel class of the thioredoxin fold proteins.