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Hsp90 as a Member of Dicarboxylate Clamp TPR Protein Interaction Network: Implication in Human Diseases and Prospect as a Drug Target

  • Rajnish Kumar
  • Bengt Winblad
  • Pavel F. PavlovEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 19)

Abstract

Heat shock protein (Hsp) 90 kDa is a widely expressed molecular chaperone and is involved in folding of broad range of client proteins, intracellular transport and degradation of damaged and misfolded proteins. The function of Hsp90 is mediated through its partner co-chaperones, which either affects the ATPase activity or directly helps Hsp90 to interact with its specific client proteins. Tetratricopeptide repeat (TPR) domain containing proteins represent a major class of co-chaperones which interact with the extreme C-terminus of Hsp90 through a dicarboxylate clamp mechanism. We have recently suggested that Hsp90 and Hsp70 molecular chaperones belong to dicarboxylate clamp protein interaction network where proteins containing similar C-terminus as that of Hsp90/Hsp70 interact with TPR motif containing proteins through dicarboxylate clamp mechanism. Recent findings suggest that several of TPR co-chaperones have been involved in variety of human diseases such as tauopathy and amyloidopathy in Alzheimer’s disease, cancer, metabolic disorders, inflammation and others. In this chapter, we discuss the potential of Hsp90 TPR containing co-chaperones as drug targets in human disorders.

Keywords

Alzheimer’s disease Dicarboxylate clamp Molecular chaperones Protein interaction network Tetratricopeptide repeat motif TPR proteins 

Abbreviations

Aha1

Activator of 90 kDa heat shock protein ATPase homolog 1

AIP

Arylhydrocarbon receptor-interacting protein

CFTR

Cystic fibrosis transmembrane conductance regulator

CHIP

C terminus of HSC70-interacting protein

CK1, CK2

Casein kinase 1 and casein kinase 2

Cyp40

Cyclophilin 40 kDa

dcTPR

Dicarboxylate clamp tetratricopeptide repeat

FKBP

FK506-binding protein

GO

Gene ontology

GR

Glucocorticoid receptor

GSK3β

Glycogen synthase kinase 3 beta

HCV

Hepatitis C virus

HOP

Hsp70-Hsp90 organizing protein

Hsp

Heat shock protein

p23

Prostaglandin E synthase 3

PP5

Protein phosphatase 5

PPIase

Peptidyl-prolyl cis-trans isomerase

PPIs

Protein-protein interactions

SGTA

Small, glutamine-rich, tetratricopeptide repeat protein alpha

Tom70

Translocase of the outer mitochondrial membrane

TPR

Tetratricopeptide repeat

Notes

Acknowledements

The work was supported by research grants from the Swedish Research Council (2015-02774, 2018-002843), Stiftelsen Olle Enqvist Byggmästare, Margareta af Ugglas Foundation, Foundation for Geriatric Diseases at Karolinska Institutet, Loo & Hans Osterman Foundation, KI Foundations, Lindhés Advokatbyrå AB Foundation, Gunvor and Josef Anérs Foundation, the Swedish Brain Foundation, Magnus Bergvalls Foundation, Gun and Bertil Stohnes Foundation, Tore Nilssons Foundation for medical research, and the Foundation for Old Servants.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rajnish Kumar
    • 1
  • Bengt Winblad
    • 1
    • 2
  • Pavel F. Pavlov
    • 1
    • 2
    Email author
  1. 1.Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division of NeurogeriatricsKarolinska InstituteSolnaSweden
  2. 2.Memory Clinic, Theme AgingKarolinska University HospitalHuddingeSweden

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