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Molecular Insight on the Relationship Between the Opposing Co‐chaperones CHIP and HOP
Author(s) -
Schisler Jonathan,
George Kathleen,
Cottingim Kelsey,
Makaroff Katherine,
Zhang Huaqun,
McDonough Holly,
Patterson Cam,
Rubel Carrie,
Page Richard
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb217
Subject(s) - hsp70 , chaperone (clinical) , phosphorylation , microbiology and biotechnology , heat shock protein , hop (telecommunications) , chemistry , biology , gene , biochemistry , computer science , medicine , computer network , pathology
Cellular chaperones and co‐chaperones maintain protein quality control (PQC) and are vital to cellular stress responses. The TPR‐containing co‐chaperones CHIP (C‐terminus of Hsp70 Interacting Protein, STUB1 ) and HOP (Hsp70 Organizing Protein, STIP1 ) are implicated in counter‐regulatory mechanisms of chaperone‐bound client proteins by promoting degradation or folding environments, respectively. To identify proteins influenced by CHIP expression, we performed gene expression arrays and protein analyses from mouse liver. We discovered that in mice lacking CHIP expression the level of hepatic HOP mRNA and protein decreased 70% compared to wild‐type tissue. 2D differential in gel electrophoresis further demonstrated that cells lacking CHIP fail to maintain HOP protein during heat shock. Our data suggest the CHIP‐HOP‐chaperone system is influenced in part by CHIP‐dependent regulation of HOP expression. In addition to CHIP affecting HOP expression, the balance between CHIP and HOP occupancy with the chaperone HSP70 is influenced by phosphorylation near the EEVD motif (PMID: 22824801). To better understand how phosphorylation influences CHIP binding to HSP70, we determined the crystal structure of the CHIP TPR bound to the non‐phosphorylated tail (A) and phosphorylated tail (B) of HSP70 at 1.9 Å and 1.4 Å, respectively. Biolayer interferometry demonstrated the phosphorylation of HSP70 decreased the binding affinity to CHIP 10‐fold. Together, these results reveal new insight into CHIP‐HOP‐chaperone signaling and the cellular stress response.