Please contact us for any questions or request for reagents for this structure.

Human NUMB-like protein, phosphotyrosine interaction domain

Click on the iSee icon to launch an enhanced annotation with interactive 3D representations and animated transitions. Please note that a web plugin (activeICM) is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available.

PDB Code 3F0W Target Class Miscellaneous Target NUMBL Alias CAG3A, CTG3a, NBL, NUMB-R, NUMBL, NUMBLIKE, NUMBR, TNRC23 Disease Area/Function neurobiology Date Deposited Oct 27 2008 Authors LEHTIO, L., MOCHE, M., ANDERSSON, J., ARROWSMITH, C.H., BERGLUND, H., BOUNTRA, C., BUSAM, R.D., COLLINS, R., DAHLGREN, L.G., EDWARDS, A.M., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., JOHANSSON, A., JOHANSSON, I., KARLBERG, T., KOTENYOVA, T., NILSSON, M.E., NYMAN, T., PERSSON, C., SAGEMARK, J., SCHUELER, H., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., WELIN, M., WIKSTROM, M., WISNIEWSKA, M., NORDLUND, P.,

About this structure

Studies of NUMBL homologues in Drosphila and mouse have shown that NUMBL is involved in nervous system development. Two human proteins NUMBL and NUMB have 57 % identity and they have been both showed to control cell number in neurogenesis (1) and they play essential roles in the asymmetric cell division together with they binding partner NOTCH1. They are both involved in maintenance of cadherin-mediated adhesion and polarity of radial glial cells during neocortical neurogenesis (2). NUMB and NUMBL share a highly similar N-terminal phosphotyrosine interaction domain whereas they differ more for the C-terminal region. NUMB and NUMBL have been shown to have overlapping functions in the regulation of cellular differentiation, proliferation, and fate decision, but they also differ as for example only NUMBL and not NUMB inhibits NF-κB signaling pathway (3). NUMBL thus provides a link between the NOTCH and NF-κB signaling pathways. Interestingly, NUMBL contains a repeat of 20 glutamines and changes in this region has been linked to schizophrenia (4).

We have solved the crystal structure of the phosphotyrosine interaction domain (5) of NUMBL. This domain is a protein-protein binding module of NUMBL and it allows NUMBL to interact with various proteins. Notably, phosphorylation or even a tyrosine does not seem to be an absolute requirement for binding to this domain. It has been shown that Drosophila NUMB is able to bind peptides in at least two different conformations (6). The present crystal structure mimics the binding mode where a strand is added to the β-sheet of NUMBL. The peptide in this case is an expression tag of the adjacent molecule in the crystal.

References

  1. Petersen, P.H., Zou, K., Hwang, J.K., Jan, Y.N. & Zhong, W. (2002) Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 419:929-34.
  2. Rasin, M.R., Gazula, V.R., et al. (2007) Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nat Neurosci. 10:819-27.
  3. Ma Q, Zhou L, Shi H, Huo K. (2008) NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation. Cell Signal. 20:1044-51.
  4. Passos Gregorio, S., Gattaz, W.F., et al. (2006) Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects. Schizophr Res. 88:275-82.
  5. van der Geer P, Pawson T. (1995) The PTB domain: a new protein module implicated in signal transduction. Trends Biochem Sci. 20:277-80.
  6. Zwahlen, C., Li, S.C., Kay, L.E., Pawson, T. & Forman-Kay, J.D. (2000) Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb. EMBO J. 19:1505-15.