Abstract
Controversy regarding the functional conservation of cereblon CUL4-type E3 ligase substrate receptor
Highlights
T cells [16] and is responsible for the cytotoxicity of human MM cells [17]
In the thalidomide binding domain (TBD) of CRBN, examination of the sequences across vertebrate species revealed that CRBN is structurally well-conserved except for three amino acids (Cys366 human to Ser369 mouse, Glu377 to Val380 mouse, and Val388 human to Ile391 mouse) [19]
Consistent with the current premise on the role of Ile391, we confirmed that Ikaros ubiquitin-mediated degradation fails to occur in mouse T cells and multiple myeloma tumor cells [19]
Summary
T cells [16] and is responsible for the cytotoxicity of human MM cells [17]. CK1α degradation is selectively targeted by lenalidomide which garners an apoptotic phenotype that is uniquely associated with clinical responses in del(5q) MDS [18]. Structural studies have demonstrated how immunomodulatory drugs form a molecular bridge between CRBN and its drug-dependent binding partner CK1α [15]. Ile391 introduces a steric hindrance that diminishes the binding of all known neo-substrates that contain a conserved β-hairpin loop in their secondary structure including CK1α, Ikaros and Aiolos [15].
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