Which protein facilitates ER protein folding by recognizing exposed hydrophobic regions?
Early folding intermediates expose hydrophobic clusters that normally bury within native core and are highly aggregation-prone in crowded ER environment at high protein concentration. Recognition of such patches is specialized function of Hsp70 family member BiP, also called GRP78 encoded by HSPA5 gene, abundant in ER lumen. Its C-terminal substrate binding domain forms beta-sandwich hydrophobic cleft with lid that binds extended stretches five to seven residues enriched in leucine, isoleucine, valine, phenylalanine and tryptophan via van der Waals contacts. ATP-bound open conformation has low affinity allowing rapid scanning of nascent chains emerging through Sec61. J-domain co-chaperones ERdj1-ERdj8 stimulate ATP hydrolysis converting to ADP-bound closed high-affinity state clamping substrate preventing aggregation and giving time for folding. Nucleotide exchange factors SIL1 and Grp170 promote ADP release allowing release and refolding attempts. Iterative cycling shields translocating chains, stabilizes unassembled antibody subunits and participates in ERAD triage maintaining solubility. Calreticulin, ERp57 and PDI focus on glycan and oxidative aspects rather than generic hydrophobic recognition, making BiP primary detector of exposed hydrophobic regions governing proteostasis and UPR sensor regulation and stress adaptation.
Ref: Mayer & Bukau, Cell Mol Life Sci 62: 2005, BiP Binding Hydrophobic Patches.