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Structural basis for intersubunit signaling in a protein disaggregating machine.

Biter AB, Lee S, Sung N, Tsai FT
Proc Natl Acad Sci U S A 109 12515-20 (2012)
Related entries: 4fct, 4fcv, 4fcw

Cited: 34 times
EuropePMC logo PMID: 22802670

Abstract

ClpB is a ring-forming, ATP-dependent protein disaggregase that cooperates with the cognate Hsp70 system to recover functional protein from aggregates. How ClpB harnesses the energy of ATP binding and hydrolysis to facilitate the mechanical unfolding of previously aggregated, stress-damaged proteins remains unclear. Here, we present crystal structures of the ClpB D2 domain in the nucleotide-bound and -free states, and the fitted cryoEM structure of the D2 hexamer ring, which provide a structural understanding of the ATP power stroke that drives protein translocation through the ClpB hexamer. We demonstrate that the conformation of the substrate-translocating pore loop is coupled to the nucleotide state of the cis subunit, which is transmitted to the neighboring subunit via a conserved but structurally distinct intersubunit-signaling pathway common to diverse AAA+ machines. Furthermore, we found that an engineered, disulfide cross-linked ClpB hexamer is fully functional biochemically, suggesting that ClpB deoligomerization is not required for protein disaggregation.

Reviews - 4fd2 mentioned but not cited (1)

  1. Structural Elements Regulating AAA+ Protein Quality Control Machines. Chang CW, Lee S, Tsai FTF. Front Mol Biosci 4 27 (2017)

Articles - 4fd2 mentioned but not cited (2)

  1. Structural basis for intersubunit signaling in a protein disaggregating machine. Biter AB, Lee S, Sung N, Tsai FT. Proc Natl Acad Sci U S A 109 12515-12520 (2012)
  2. Two local minima for structures of [4Fe-4S] clusters obtained with density functional theory methods. Jafari S, Ryde U, Irani M. Sci Rep 13 10832 (2023)


Reviews citing this publication (9)

  1. Protein rescue from aggregates by powerful molecular chaperone machines. Doyle SM, Genest O, Wickner S. Nat Rev Mol Cell Biol 14 617-629 (2013)
  2. Allosteric conformational barcodes direct signaling in the cell. Nussinov R, Ma B, Tsai CJ, Csermely P. Structure 21 1509-1521 (2013)
  3. Molecular chaperones: guardians of the proteome in normal and disease states. Jeng W, Lee S, Sung N, Lee J, Tsai FT. F1000Res 4 F1000 Faculty Rev-1448 (2015)
  4. Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem. Aguado A, Fernández-Higuero JA, Moro F, Muga A. Arch Biochem Biophys 580 121-134 (2015)
  5. Comparative Analysis of the Structure and Function of AAA+ Motors ClpA, ClpB, and Hsp104: Common Threads and Disparate Functions. Duran EC, Weaver CL, Lucius AL. Front Mol Biosci 4 54 (2017)
  6. A History of Molecular Chaperone Structures in the Protein Data Bank. Bascos NAD, Landry SJ. Int J Mol Sci 20 E6195 (2019)
  7. Structural mechanisms of chaperone mediated protein disaggregation. Sousa R. Front Mol Biosci 1 12 (2014)
  8. Assessing heterogeneity in oligomeric AAA+ machines. Sysoeva TA. Cell Mol Life Sci 74 1001-1018 (2017)
  9. Mitochondrial AAA proteases: A stairway to degradation. Steele TE, Glynn SE. Mitochondrion 49 121-127 (2019)

Articles citing this publication (22)

  1. Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. Gates SN, Yokom AL, Lin J, Jackrel ME, Rizo AN, Kendsersky NM, Buell CE, Sweeny EA, Mack KL, Chuang E, Torrente MP, Su M, Shorter J, Southworth DR. Science 357 273-279 (2017)
  2. Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction. Rosenzweig R, Moradi S, Zarrine-Afsar A, Glover JR, Kay LE. Science 339 1080-1083 (2013)
  3. Divergent protein motifs direct elongation factor P-mediated translational regulation in Salmonella enterica and Escherichia coli. Hersch SJ, Wang M, Zou SB, Moon KM, Foster LJ, Ibba M, Navarre WW. mBio 4 e00180-13 (2013)
  4. The mechanism of Torsin ATPase activation. Brown RS, Zhao C, Chase AR, Wang J, Schlieker C. Proc Natl Acad Sci U S A 111 E4822-31 (2014)
  5. Altered intersubunit communication is the molecular basis for functional defects of pathogenic p97 mutants. Tang WK, Xia D. J Biol Chem 288 36624-36635 (2013)
  6. ClpB N-terminal domain plays a regulatory role in protein disaggregation. Rosenzweig R, Farber P, Velyvis A, Rennella E, Latham MP, Kay LE. Proc Natl Acad Sci U S A 112 E6872-81 (2015)
  7. Structural Basis of ATP Hydrolysis and Intersubunit Signaling in the AAA+ ATPase p97. Hänzelmann P, Schindelin H. Structure 24 127-139 (2016)
  8. Nucleotide-induced asymmetry within ATPase activator ring drives σ54-RNAP interaction and ATP hydrolysis. Sysoeva TA, Chowdhury S, Guo L, Nixon BT. Genes Dev 27 2500-2511 (2013)
  9. Structural basis for the disaggregase activity and regulation of Hsp104. Heuck A, Schitter-Sollner S, Suskiewicz MJ, Kurzbauer R, Kley J, Schleiffer A, Rombaut P, Herzog F, Clausen T. Elife 5 e21516 (2016)
  10. Insights into the mechanism and regulation of the CbbQO-type Rubisco activase, a MoxR AAA+ ATPase. Tsai YC, Ye F, Liew L, Liu D, Bhushan S, Gao YG, Mueller-Cajar O. Proc Natl Acad Sci U S A 117 381-387 (2020)
  11. Structural dynamics of the MecA-ClpC complex: a type II AAA+ protein unfolding machine. Liu J, Mei Z, Li N, Qi Y, Xu Y, Shi Y, Wang F, Lei J, Gao N. J Biol Chem 288 17597-17608 (2013)
  12. ClpB dynamics is driven by its ATPase cycle and regulated by the DnaK system and substrate proteins. Aguado A, Fernández-Higuero JA, Cabrera Y, Moro F, Muga A. Biochem J 466 561-570 (2015)
  13. ClpB chaperone passively threads soluble denatured proteins through its central pore. Nakazaki Y, Watanabe YH. Genes Cells 19 891-900 (2014)
  14. Adenosine diphosphate restricts the protein remodeling activity of the Hsp104 chaperone to Hsp70 assisted disaggregation. Kłosowska A, Chamera T, Liberek K. Elife 5 e15159 (2016)
  15. Examination of polypeptide substrate specificity for Escherichia coli ClpB. Li T, Lin J, Lucius AL. Proteins 83 117-134 (2015)
  16. Analysis of the cooperative ATPase cycle of the AAA+ chaperone ClpB from Thermus thermophilus by using ordered heterohexamers with an alternating subunit arrangement. Yamasaki T, Oohata Y, Nakamura T, Watanabe YH. J Biol Chem 290 9789-9800 (2015)
  17. Crowding activates ClpB and enhances its association with DnaK for efficient protein aggregate reactivation. Martín I, Celaya G, Alfonso C, Moro F, Rivas G, Muga A. Biophys J 106 2017-2027 (2014)
  18. Covalently linked HslU hexamers support a probabilistic mechanism that links ATP hydrolysis to protein unfolding and translocation. Baytshtok V, Chen J, Glynn SE, Nager AR, Grant RA, Baker TA, Sauer RT. J Biol Chem 292 5695-5704 (2017)
  19. Structural and mechanistic insights into Hsp104 function revealed by synchrotron X-ray footprinting. Sweeny EA, Tariq A, Gurpinar E, Go MS, Sochor MA, Kan ZY, Mayne L, Englander SW, Shorter J. J Biol Chem 295 1517-1538 (2020)
  20. Aqueous peat extract exposes rhizobia to sub-lethal stress which may prime cells for improved desiccation tolerance. Atieno M, Wilson N, Casteriano A, Crossett B, Lesueur D, Deaker R. Appl Microbiol Biotechnol 102 7521-7539 (2018)
  21. The Symbiotic Performance of Chickpea Rhizobia Can Be Improved by Additional Copies of the clpB Chaperone Gene. Paço A, Brígido C, Alexandre A, Mateos PF, Oliveira S. PLoS One 11 e0148221 (2016)
  22. Deciphering the mechanism and function of Hsp100 unfoldases from protein structure. Lee G, Kim RS, Lee SB, Lee S, Tsai FTF. Biochem Soc Trans 50 1725-1736 (2022)


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