8.A.162. The Cereblon (CRBN) Family It maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons (Higgins et al. 2008, Choi et al. 2018). It probably functions by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (Higgins et al. 2008). It may also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism. The IMiD target, CRBN, determines HSP90 activity toward the proper insertion of transmembrane proteins essential in multiple myeloma (Heider et al. 2021). IMiDs, which disrupt the interaction of CRBN with HSP90, folds the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity.
References:
Choi, T.Y., S.H. Lee, Y.J. Kim, J.R. Bae, K.M. Lee, Y. Jo, S.J. Kim, A.R. Lee, S. Choi, L.M. Choi, S. Bang, M.R. Song, J. Chung, K.J. Lee, S.H. Kim, C.S. Park, and S.Y. Choi. (2018). Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel. J. Neurosci. 38: 3571-3583.
Heider, M., R. Eichner, J. Stroh, V. Morath, A. Kuisl, J. Zecha, J. Lawatscheck, K. Baek, A.K. Garz, M. Rudelius, F.C. Deuschle, U. Keller, S. Lemeer, M. Verbeek, K.S. Götze, A. Skerra, W.A. Weber, J. Buchner, B.A. Schulman, B. Kuster, V. Fernández-Sáiz, and F. Bassermann. (2021). The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Mol. Cell 81: 1170-1186.e10.
Higgins, J.J., J. Hao, B.E. Kosofsky, and A.M. Rajadhyaksha. (2008). Dysregulation of large-conductance Ca²⁺-activated K⁺ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics 9: 219-223.
Examples:
TC#	Name	Organismal Type	Example
8.A.162.1.1	*Cereblon, CRBN, of 442 aas and 0, 1, or 2 TMSs. See family description for function. CRBN determines HSP90 activity toward transmembrane proteins (Heider et al.* 2021).**		CRBN of Homo sapiens

8.A.162.1.2	Uncharacterized protein of 518 aas.		UP of Dunaliella salina

8.A.162.1.3	Uncharacterized protein of 157 aas and 0 or 1 TMS.		UP of Desulfohalobium retbaense

8.A.162.1.4	LON peptidase substrate-binding domain-containing protein of 233 aas and one N-terminal TMS.		Lon domain of Actinocatenispora thailandica

8.A.162.1.5	Protein cereblon isoform X1 of 183 aas and possibly 2 TMSs, one at the N-terminus and one near the C-terminus of the protein.		Cereblon of Octopus sinensis

8.A.162.1.6	Uncharacterized protein of 121 aas and possibly one TMS.		UP of Leptospira sarikeiensis

8.A.162.1.7	Uncharacterized protein of 181 aas and 1 N-terminal TMS.		UP of Scleropages formosus

8.A.162.1.8	Peptidase S16 of 231 aas and 1 N-terminal TMS plus two additional possible TMSs, that might be within two sequential repeat units.		Peptidase S16 of α-proteobacteria bacterium PA2 (algae metagenome)