Fig. 10: A working model for b0,+AT-rBAT biogenesis and its defects in cystinuria.
a Model of super-dimer assembly in the ER. The initial step is the heterodimerization of b0,+AT and core-glycosylated rBAT (denoted as rBATc). Since b0,+AT is known to be required for oxidative folding and N-glycan maturation of rBAT12, defects in the b0,+AT expression itself (e.g., b0,+AT G105R) or the b0,+AT–rBAT interaction (e.g., rBAT L89P) would interfere with the initial assembly process and thus prevent glycan maturation. In the latter step, two molecules of b0,+AT–rBAT assemble to form a super-dimer, which requires Ca2+ binding. Mutations that prevent super-dimerization, such as rBAT T216M and the Ca2+-binding site mutants, abolish this step. Incomplete complexes cannot pass the ER quality control. It is noted that rBAT R365W and M467T can form super-dimers to some extent but are probably less stable than the wild-type, due to their positions in the subdomain interfaces. b In the Golgi apparatus, the super-dimeric b0,+AT–rBAT undergoes full glycan maturation (mature glycans are depicted by longer branches). As rBAT R365W and M467T can form super-dimers, they get partially maturated. c Upon correct maturation, super-dimeric b0,+AT–rBAT will be trafficked to the apical membrane of epithelial cells. Microvilli consist of numerous membrane protrusions, consistent with the curved lipid bilayer of b0,+AT–rBAT. d Non-type I mutations (e.g., b0,+AT V170M) abolish transport activity.
