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The binding stoichiometry of CIN85 SH3 domain A and Cbl-b

Nature Structural & Molecular Biology volume 15, pages 890–891 (2008)Cite this article

To the editor:

Receptor tyrosine kinase (RTK) activation results in the initiation of several crucial cellular biological processes, including proliferation, adhesion and apoptosis1. However, for normal cell function, RTK activity must be tightly regulated and controlled either by its inhibition or through endocytic trafficking and degradation2. An important adaptor protein that has a key role in the latter process is the human Cbl-interacting protein of 85 kDa, CIN85 (also known as SETA, Ruk or SH3KBP1)3. The main known function of CIN85 is to downregulate RTKs and facilitate endocytosis by interacting with the endophilin-associated ubiquitin ligase Cbl proteins3,4. Complex formation between CIN85 and Cbl proteins takes place through CIN85's three SH3 domains (referred to as CIN85A, B and C). The interaction is meditated via atypical proline-arginine motifs of the form PXXXPR (where X is any residue) located in the C-terminal region of Cbl proteins5,6,7. In vitro studies of the binding of either isolated or linked CIN85 SH3 domains provide an important insight into the mechanism of recognition and recruitment of Cbl proteins to these domains. Furthermore, because CIN85 exists as a dimer and/or tetramer in vivo (based on the N-terminal coiled-coil interactions between monomers)8, in vitro studies provide an understanding of the implications of such oligomerization states of the protein in achieving its function and, in particular, its interaction with Cbl proteins. The existence of such oligomeric states of the protein are likely to be important in the function of CIN85 for several reasons, for example, in ensuring high local concentration of the protein, in maximizing the clustering of Cbl proteins via formation of multimeric complexes, or simply for the folding and stability of the protein under conditions of cell stress.

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Figure 1: (a) X-ray structure of CIN85A–Cbl-b heterotrimeric complex.
Figure 2: Overlaid 1H-15N HSQC spectra of apo-CIN85A (blue) and CIN85A in complex with Cbl-b peptide (red).

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Abdessamad Ababou & John E Ladbury

  2. Department of Biochemistry, University of Leicester, University Road, Leicester, LE1 7RH, UK

    Mark Pfuhl

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  1. Abdessamad Ababou
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  2. Mark Pfuhl
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  3. John E Ladbury
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Ababou, A., Pfuhl, M. & Ladbury, J. The binding stoichiometry of CIN85 SH3 domain A and Cbl-b. Nat Struct Mol Biol 15, 890–891 (2008). https://doi.org/10.1038/nsmb0908-890

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