Hendershot: ER chaperones

The ER chaperones and folding enzymes bind and release nascent proteins in order to promote proper folding and subunit assembly. This cycle of binding is a carefully controlled process, which prevents the aggregation of unfolded regions on proteins, helps guide proper folding, and ensures that only completely folded and assembled proteins are transported through the cell. Two distinct chaperone groups assist and monitor the maturation of secretory pathway proteins:  the calnexin/calreticulin family and the BiP or Hsp70 family.  We have primarily focused on the ER Hsp70 family members BiP and GRP170.  BiP is known to be a master regulator of ER functions including maintaining the permeability barrier of the ER during protein translocation, assisting protein folding, targeting unfolded proteins for degradation, contributing to ER calcium stores, and regulating a signal transduction protein that is activated when protein folding is compromised in the ER.  Except for binding calcium, all of these functions require BiP’s ATPase activity. A number of resident ER proteins that regulate this activity have been identified recently, including five ER DnaJ homologues, which stimulate ATP hydrolysis and stabilize the binding of BiP to unfolded proteins, and two nucleotide exchange factors that help release the chaperone so proteins can complete their folding.  Mutations in BAP/Sil1p, a nucleotide exchange factor for BiP, have been linked to Marinesco-Sjogren Syndrome, a genetic form of ataxia that arises due to the accumulation of unfolded proteins in cerebellar Purkinje cells.  The aim of our current studies are: 1) to determine the contribution of the different DnaJ proteins in regulating BiP’s various functions, 2) to determine the contribution of BAP vs GRP170 in regulating BiP’s activity in different tissues and with various unfolded substrates.