Ubiquitin-Mediated Proteasomal Degradation of ABC Transporters: a New Aspect of Genetic Polymorphisms and Clinical Impacts

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

“…This discrepancy may result from the fundamental differences in protein topography; namely, ABCG2 is a half-transporter and CFTR is not. This difference translates into the apparent failure of ΔF142 ABCG2 to dimerize and fold properly, a failure with important consequences for trafficking and expression (11,26). We probed this idea by introducing mutations in the first ICL at residue K473, the residue that we believe to be functionally homologous to R1070 in CFTR ICL4, and found that mutations of K473 could disrupt ABCG2 dimerization much like ΔF142.…”

“…Multiple groups reported that the Q141K mutation decreases protein expression and, coincidentally, xenotoxin transport function (11)(12)(13)(14)(15)(16). This decrease of expression and function appears to be partially caused by the enhancement of the Q141K mutant's susceptibility to proteasomal degradation (11)(12)(13).…”

Defining the blanks – Pharmacochaperoning of SLC6 transporters and ABC transporters

“…A systematic survey of non-synonymous mutations indicates that misfolding as an underlying mechanism of ABC protein deficiencies might be more prevalent than expected. Evidence for the effect of mutations and non-synonymous SNPs on protein trafficking, maturation, or ER associated degradation has been provided for at least the following members of the human ABC family: ABCA1, ABCA3, ABCA4, ABCB1, ABCB4, ABCB11, ABCC2, ABCC4, ABCC7, ABCC8, ABCC11 and ABCG2 (reviewed in Nakagawa et al [97]). Undoubtedly, ubiquitin-mediated proteasomal degradation of ABC transporters due to incomplete folding is recognized as an important pathogenetic principle for diseases associated with ABC protein deficiency beyond the well-appreciated paradigm of cystic fibrosis.…”

Pharmacological correction of misfolding of ABC proteins

“…The available evidence indicates misfolding and premature degradation caused by missense mutations as a significant cause of membrane protein deficiencies [1]. Disease causing mutations in several human ABC proteins, including among others ABCA1 (Tangier disease), ABCB4 (progressive familial intrahepatic cholestasis type 3), ABCB11 (progressive familial intrahepatic cholestasis type 2), ABCC2 (Dubin-Johnson syndrome), ABCC7 (cystic fibrosis), ABCC8 (hyperinsulinemic hypoglycemia of infancy) and ABCG2 (gout), have been linked to aberrant folding, retrotranslocation of proteins into the cytoplasm and subsequent proteasomal degradation [1]. …”