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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

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Heat Shock Protein 90 in Human Diseases and Disorders

Part of the book series: Heat Shock Proteins ((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.

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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

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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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Authors and Affiliations

  1. Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institute, Solna, Sweden

    Rajnish Kumar, Bengt Winblad & Pavel F. Pavlov

  2. Memory Clinic, Theme Aging, Karolinska University Hospital, Huddinge, Sweden

    Bengt Winblad & Pavel F. Pavlov

Authors
  1. Rajnish Kumar
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  2. Bengt Winblad
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  3. Pavel F. Pavlov
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Corresponding author

Correspondence to Pavel F. Pavlov .

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Editors and Affiliations

  1. Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Kumar, R., Winblad, B., Pavlov, P.F. (2019). Hsp90 as a Member of Dicarboxylate Clamp TPR Protein Interaction Network: Implication in Human Diseases and Prospect as a Drug Target. In: Asea, A., Kaur, P. (eds) Heat Shock Protein 90 in Human Diseases and Disorders. Heat Shock Proteins, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-23158-3_14

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