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Fig. 1 | BMC Biology

Fig. 1

From: Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation

Fig. 1

Model depicting linker helix (LH)-mediated regulation of Cbl ligase. a Domains of Cbl’s N-terminal ubiquitin ligase region. A blue rectangle and navy wavy line correspondingly depict the TKBD and its substrate-binding site. The LHR and its components are indicated with LL1 coloured purple, LL2 green and LH yellow. A yellow hexagon depicts the LH Tyr. The RING is coloured orange with the two loops representing the E2-binding site. b Model of unphosphorylated Cbl coloured as in (a). When Tyr371 is unphosphorylated, the LH is clamped to the TKBD and movement of the RING restricted to the TKBD face opposing the substrate-binding site. Rotation about LL2 allows Cbl to fluctuate between an autoinhibited state where the E2-binding site is occluded (left) and a catalytically competent state where E2 is able to bind (right). c Model of phosphorylated Cbl coloured as in (a). A brown hexagon and circle represent the phosphorylated LH Tyr. When Tyr371 is phosphorylated, the LH clamps into the RING domain and LL1 rotates 180°, juxtaposing the RING domain and substrate-binding face of the TKBD. The Tyr371 binding site on the TKBD cannot accommodate a phosphate moiety, thereby eliminating the LH-TKBD interaction. Whether the RING domain is flexible in solution is unknown. d Model depicting possible states of Cbl Tyr 371 mutants coloured as in (a). The LH Tyr371 mutant is shown as an X in a red square. Cbl Y371X mutants are predicted to favour different states depending on the chemical nature of the substitution. Less disruptive mutants are expected to maintain the unphosphorylated equilibrium (left and middle), whereas more disruptive mutants are expected to perturb the LH-TKBD interaction, leaving the RING in an open, catalytically competent conformation with greater access to space surrounding the TKBD (right)

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