InterPro domain: IPR036537

Cbl (Casitas B-lineage lymphoma) is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface.

The N-terminal region of Cbl contains a Cbl-type phosphotyrosine-binding (Cbl-PTB) domain, which is composed of three evolutionarily conserved domains: an N-terminal four-helix bundle (4H) domain, an EF hand-like calcium-binding domain, and a divergent SH2-like domain. The calcium-bound EF-hand wedges between the 4H and SH2 domains, and roughly determines their relative orientation. The Cbl-PTB domain has also been named Cbl N-terminal (Cbl-N) or tyrosine kinase binding (TKB) domain [ 1 , 2 ].

The N-terminal 4H domain contains four long alpha-helices. The C and D helices in this domain pack against the adjacent EF-hand-like domain, and a highly conserved loop connecting the A and B helices contacts the SH2-like domain. The EF-hand motif is similar to classical EF-hand proteins. The SH2-likedomain retains the general helix-sheet-helix architecture of the SH2 fold, but lacks the secondary beta-sheet, comprising beta-strands D', E and F, and also a prominent BG loop [ 3 ].

This entry represents the N-terminal four-helical bundle domain superfamily. This domain can also be found in the N terminus of mammalian MLKL, a pseudokinase essential for TNF-alpha-induced necroptosis [ 3 ]. The four-helical bundle (NB) domain of MLK is involved in oligomerization to facilitate plasma membrane targeting through the low-affinity binding of NB to phosphorylated inositol polar head groups of phosphatidylinositol phosphate (PIP) phospholipids [ 4 , 5 ].

1. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 398, 84-90
2. A Dictyostelium homologue of the metazoan Cbl proteins regulates STAT signalling. J. Cell. Sci. 121, 3524-30
3. MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis. Proc. Natl. Acad. Sci. U.S.A. 114, E7450-E7459
4. Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis. Mol. Cell 61, 589-601
5. A tale of two domains - a structural perspective of the pseudokinase, MLKL. FEBS J. 282, 4268-78