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Role of the CHIP/Hsp70 Protein Quality Control Complex as an Information Processor
Author(s) -
Page Richard C
Publication year - 2016
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.30.1_supplement.1063.1
Subject(s) - hsp70 , ubiquitin ligase , chaperone (clinical) , ubiquitin , protein folding , microbiology and biotechnology , chip , hsp90 , biophysics , chemistry , biology , biochemistry , heat shock protein , computer science , gene , medicine , telecommunications , pathology
Intracellular protein quality control fulfills the need for a rapid and robust response to protein misfolding that is ubiquitous in human physiology. Defects in protein quality control pathways can lead to a wide range of diseases including cystic fibrosis and recessive hereditary cerebellar ataxias. Within the field of protein quality control, the ubiquitin ligase CHIP and chaperone Hsp70 play crucial roles in directing misfolded client proteins to either the refolding, or degradative pathways. Together, CHIP and Hsp70 form a complex that exhibits functions characteristic of an information processor. Our results suggest that the complex takes inputs from both dynamic motions and posttranslational modifications in determining the fate of the misfolded protein. Guided by our 2.91 Å resolution structure of the TPR domain of CHIP in complex with the α‐helical “lid” subdomain and unstructured “tail” of Hsc70, we can now assemble full‐length models of the CHIP/Hsp70 complex. This structural data, combined with nuclear magnetic resonance, small angle X‐ray scattering, electron paramagnetic resonance, and biochemical data identify the mechanisms by which the function of the CHIP/Hsp70 complex is regulated. Surprisingly, the CHIP‐TPR interacts with determinants within both the Hsc70‐lid subdomain and the C‐terminal GPTIEEVD motif of the tail, exhibiting a novel mode of chaperone‐TPR domain interaction. This interaction mode provides sensitivity to posttranslational modifications of CHIP and Hsp70 and enables dynamic motions within CHIP to modulate activity of Hsp70. Support or Funding Information Supported by Burroughs Wellcome Foundation Collaborative Travel Research Grant #1014031