Fig. 7

Cartoon depicting the function of MANF as a nucleotide exchange inhibitor (NEI) for BiP. ER-localized BiP undergoes a J-protein- and nucleotide exchange factor (NEF)-dependent chaperone cycle (dark gray). MANF can interact with substrate-bound BiP in the ADP state, in which the nucleotide-binding domain (NBD) and substrate-binding domain (SBD) are undocked, to slow down nucleotide exchange and substrate dissociation (dotted line). By analogy to the role of the cytosolic Hip protein, MANF-mediated stabilization of certain BiP–client complexes may enhance the efficiency of client transfer to downstream ER quality control effectors. These may include other chaperone systems (e.g., Grp94), degradation via ERAD, or factors involved in assembly of multimeric complexes. The binding of MANF via its SAP domain to the NBD of BiP allows the simultaneous action of NEFs and thereby adds an additional layer to the modulation of BiP’s functional cycle