Fig. 6.

Proposed model of UPR induction, mutation structural impact and GLA residual activity. In wild type condition, α-Gal A enters the secretory pathway to reach its lysosomal localization. At steady state the protein is almost completely localized in the lysosome and active. Misfolded mutants reported to have residual activity and low structural impact are partially ER retained inducing ER stress and UPR to an extent that is inversely correlated with ER retention and residual enzymatic activity. Mutants shown to have high structural impact and no residual activity are fully retained in the ER and induce robust ER stress and UPR.