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Human SH3 domain of LIM and SH3 domain protein 1

PDB Code 3I35 Target Class Cell-type specific expression Target LASP1 Alias Lasp-1, LASP1, MLN50 Disease Area/Function cancer, signalling Date Deposited Jun 30 2009 Authors Siponen, M.I., Roos, A.K., Arrowsmith, C.H., Berglund, H., Bountra, C., Collins, R., Edwards, A.M., Flodin, S., Flores, A., Graslund, S., Hammarstrom, M., Johansson, A., Johansson, I., Karlberg, T., Kotenyova, T., Kotzsch, A., Kragh Nielsen, T. Moche, M., Nyman, T., Persson, C., Sagemark, J., Schueler, H., Schutz, P., Thorsell, A.G., Tresaugues, L., Van Den Berg, S., Weigelt, J., Welin, M. Wisniewska, M., Nordlund, P.

About this structure

LIM and SH3 protein 1 (LASP1) was first identified in a cDNA library from human breast cancer cells (1). The gene is expressed at a basal level in normal tissue but found to be upregulated in several cancers. It is not clear whether the gene product has a positive or negative role in tumour progression as conflicting results are reported (2). The actual function of LASP1 is not yet known but it plays an important role in regulating actin-based, cytoskeletal activities. Especially in leading edges of migrating cells (3).

The first characterisation of the gene showed that it can be divided into 2 main domains; one N-terminal LIM motif and one C-terminal src homology 3 (SH3) domain (4). LIM domains are found in a number of proteins where they aid protein-protein interactions by introducing a binding interface. The binding partner for the LASP1 LIM domain has not been identified but from the sequence DNA binding is also a possibility (3). The sequence in between the two main domains contains two short nebulin-like repeats, each comprised of 35 residues. These repeats allow LASP1 to bind to F-actin. SH3 domains are involved in protein-protein interactions where they recognise proline rich sequences. The LASP1 SH3 domain has been found to associate with the proteins palladin, prointerleukin-16, and zyxin to mention a few. Both palladin and zyxin are involved in cytoskeletal organization (5, 6).

We have determined the structure of the LASP1 SH3 domain to 1.4 Å resolution (PDB accession code 3I35). It shows a characteristic SH3 fold consisting of 56 residues arranged as two anti-parallel beta sheets. The plate like crystals belonged to the rather unusual space group P2 and contained only one molecule in the asymmetric unit.

References

  1. Tomasetto C, Regnier C, Moog-Lutz C, Mattei MG, Chenard MP, Lidereau R, Basset P, Rio MC: Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics 1995, 28(3):367-376.
  2. Zhang H, Chen X, Bollag WB, Bollag RJ, Sheehan DJ, Chew CS: Lasp1 gene disruption is linked to enhanced cell migration and tumor formation. Physiol Genomics. 2009, 38(3):372-85.
  3. Grunewald TG, Butt E. The LIM and SH3 domain protein family: structural proteins or signal transducers or both? Mol Cancer. 2008 Apr 17;7:31.
  4. Tomasetto C, Moog-Lutz C, Regnier CH, Schreiber V, Basset P, Rio MC: Lasp-1 (MLN 50) defines a new LIM protein subfamily characterized by the association of LIM and SH3 domains. FEBS Lett 1995, 373(3):245-249.
  5. Rachlin AS, Otey CA: Identification of palladin isoforms and characterization of an isoform-specific interaction between Lasp-1 and palladin. J Cell Sci 2006, 119(6):995-1004.
  6. Li B, Zhuang L, Trueb B: Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1. J Biol Chem 2004, 279(19):20401-20410.