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Article: The N-terminal arm of small heat shock proteins is important for both chaperone activity and substrate specificity.

Basha, Eman / Friedrich, Kenneth L / Vierling, Elizabeth

2006 Volume 281, Issue 52, Page(s) 39943–39952

Abstract: Small heat shock proteins (sHSPs) are a ubiquitous class of molecular chaperones that interacts with substrates to prevent their irreversible insolubilization during denaturation. How sHSPs interact with substrates remains poorly defined. To investigate ... ...

Abstract	Small heat shock proteins (sHSPs) are a ubiquitous class of molecular chaperones that interacts with substrates to prevent their irreversible insolubilization during denaturation. How sHSPs interact with substrates remains poorly defined. To investigate the role of the conserved C-terminal alpha-crystallin domain versus the variable N-terminal arm in substrate interactions, we compared two closely related dodecameric plant sHSPs, Hsp18.1 and Hsp16.9, and four chimeras of these two sHSPs, in which all or part of the N-terminal arm was switched. The efficiency of substrate protection and formation of sHSP-substrate complexes by these sHSPs with three different model substrates, firefly luciferase, citrate synthase, and malate dehydrogenase (MDH) provide new insights into sHSP/substrate interactions. Results indicate that different substrates have varying affinities for different domains of the sHSP. For luciferase and citrate synthase, the efficiency of substrate protection was determined by the identity of the N-terminal arm in the chimeric proteins. In contrast, for MDH, efficient protection clearly required interactions with the alpha-crystallin domain in addition to the N-terminal arm. Furthermore, we show that sHSP-substrate complexes with varying stability and composition can protect substrate equally, and substrate protection is not correlated with sHSP oligomeric stability for all substrates. Protection of MDH by the dimeric chimera composed of the Hsp16.9 N-terminal arm and Hsp18.1 alpha-crystallin domain supports the model that a dimeric form of the sHSP can bind and protect substrate. In total, results demonstrate that sHSP-substrate interactions are complex, likely involve multiple sites on the sHSP, and vary depending on substrate.
MeSH term(s)	Amino Acid Sequence ; Citrate (si)-Synthase/metabolism ; Dimerization ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/physiology ; Hot Temperature ; Luciferases/metabolism ; Malate Dehydrogenase/metabolism ; Models, Molecular ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Molecular Chaperones/physiology ; Molecular Sequence Data ; Molecular Weight ; Mutant Chimeric Proteins/chemical synthesis ; Mutant Chimeric Proteins/metabolism ; Mutant Chimeric Proteins/physiology ; Pisum sativum/chemistry ; Pisum sativum/genetics ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Peptide Fragments/physiology ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Plant Proteins/physiology ; Protein Binding/genetics ; Protein Structure, Tertiary/genetics ; Solubility ; Substrate Specificity ; Triticum/chemistry ; Triticum/genetics ; alpha-Crystallins/physiology
Chemical Substances	HSP16.9 protein, Triticum aestivum ; HSP18 protein, plant ; Heat-Shock Proteins ; Molecular Chaperones ; Mutant Chimeric Proteins ; Peptide Fragments ; Plant Proteins ; alpha-Crystallins ; Malate Dehydrogenase (EC 1.1.1.37) ; Luciferases (EC 1.13.12.-) ; Citrate (si)-Synthase (EC 2.3.3.1)
Language	English
Publishing date	2006-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M607677200
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Article: The N-terminal Arm of Small Heat Shock Proteins Is Important for Both Chaperone Activity and Substrate Specificity

Basha, Eman / Friedrich, Kenneth L / Vierling, Elizabeth

Journal of biological chemistry. 2006 Dec. 29, v. 281, no. 52

2006

Abstract	Small heat shock proteins (sHSPs) are a ubiquitous class of molecular chaperones that interacts with substrates to prevent their irreversible insolubilization during denaturation. How sHSPs interact with substrates remains poorly defined. To investigate the role of the conserved C-terminal α-crystallin domain versus the variable N-terminal arm in substrate interactions, we compared two closely related dodecameric plant sHSPs, Hsp18.1 and Hsp16.9, and four chimeras of these two sHSPs, in which all or part of the N-terminal arm was switched. The efficiency of substrate protection and formation of sHSP-substrate complexes by these sHSPs with three different model substrates, firefly luciferase, citrate synthase, and malate dehydrogenase (MDH) provide new insights into sHSP/substrate interactions. Results indicate that different substrates have varying affinities for different domains of the sHSP. For luciferase and citrate synthase, the efficiency of substrate protection was determined by the identity of the N-terminal arm in the chimeric proteins. In contrast, for MDH, efficient protection clearly required interactions with the α-crystallin domain in addition to the N-terminal arm. Furthermore, we show that sHSP-substrate complexes with varying stability and composition can protect substrate equally, and substrate protection is not correlated with sHSP oligomeric stability for all substrates. Protection of MDH by the dimeric chimera composed of the Hsp16.9 N-terminal arm and Hsp18.1 α-crystallin domain supports the model that a dimeric form of the sHSP can bind and protect substrate. In total, results demonstrate that sHSP-substrate interactions are complex, likely involve multiple sites on the sHSP, and vary depending on substrate.
Language	English
Dates of publication	2006-1229
Size	p. 39943-39952.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: The ubiquitin signal: assembly, recognition and termination. Symposium on ubiquitin and signaling.

Wilkinson, Keith D / Ventii, Karen H / Friedrich, Kenneth L / Mullally, James E

EMBO reports

2005 Volume 6, Issue 9, Page(s) 815–820

MeSH term(s)	Models, Molecular ; Peptide Hydrolases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Processing, Post-Translational/physiology ; Protein Structure, Tertiary ; Signal Transduction/physiology ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligase Complexes/metabolism
Chemical Substances	Ubiquitin ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Peptide Hydrolases (EC 3.4.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2005-08-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.1038/sj.embor.7400506
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Article: Interactions between small heat shock protein subunits and substrate in small heat shock protein-substrate complexes.

Friedrich, Kenneth L / Giese, Kim C / Buan, Nicole R / Vierling, Elizabeth

The Journal of biological chemistry

2003 Volume 279, Issue 2, Page(s) 1080–1089

Abstract: Small heat shock proteins (sHSPs) are dynamic oligomeric proteins that bind unfolding proteins and protect them from irreversible aggregation. This binding results in the formation of sHSP-substrate complexes from which substrate can later be refolded. ... ...

Abstract	Small heat shock proteins (sHSPs) are dynamic oligomeric proteins that bind unfolding proteins and protect them from irreversible aggregation. This binding results in the formation of sHSP-substrate complexes from which substrate can later be refolded. Interactions between sHSP and substrate in sHSP-substrate complexes and the mechanism by which substrate is transferred to ATP-dependent chaperones for refolding are poorly defined. We have established C-terminal affinity-tagged sHSPs from a eukaryote (pea HSP18.1) and a prokaryote (Synechocystis HSP16.6) as tools to investigate these issues. We demonstrate that sHSP subunit exchange for HSP18.1 and HSP16.6 is temperature-dependent and rapid at the optimal growth temperature for the organism of origin. Increasing the ratio of sHSP to substrate during substrate denaturation decreased sHSP-substrate complex size, and accordingly, addition of substrate to pre-formed sHSP-substrate complexes increased complex size. However, the size of pre-formed sHSP-substrate complexes could not be reduced by addition of more sHSP, and substrate could not be observed to transfer to added sHSP, although added sHSP subunits continued to exchange with subunits in sHSP-substrate complexes. Thus, although some number of sHSP subunits within complexes remain dynamic and may be important for complex structure/solubility, association of substrate with the sHSP does not appear to be similarly dynamic. These observations are consistent with a model in which ATP-dependent chaperones associate directly with sHSP-bound substrate to initiate refolding.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Bacterial Proteins ; Cell Division ; Chromatography ; Cyanobacteria/metabolism ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli/metabolism ; Heat-Shock Proteins/chemistry ; Heat-Shock Proteins/metabolism ; Luciferases/metabolism ; Pisum sativum/metabolism ; Plant Proteins ; Protein Binding ; Protein Folding ; Temperature ; Time Factors
Chemical Substances	Bacterial Proteins ; HSP18 protein, plant ; Heat-Shock Proteins ; Plant Proteins ; heat-shock protein 16.6, Synechocystis ; hsp18 protein, bacteria ; Adenosine Triphosphate (8L70Q75FXE) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2003-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M311104200
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Article ; Online: BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.

Ventii, Karen H / Devi, Narra S / Friedrich, Kenneth L / Chernova, Tatiana A / Tighiouart, Mourad / Van Meir, Erwin G / Wilkinson, Keith D

Cancer research

2008 Volume 68, Issue 17, Page(s) 6953–6962

Abstract: BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have shown for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can ... ...

Abstract	BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have shown for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated BAP1 mutants are deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we show that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle, speeding the progression through the G(1)-S checkpoint, and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Because deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anticancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Cycle ; Cell Division ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Female ; Humans ; Mice ; Mice, Nude ; Molecular Sequence Data ; Sequence Homology, Amino Acid ; Tumor Suppressor Proteins/chemistry ; Tumor Suppressor Proteins/metabolism ; Tumor Suppressor Proteins/physiology ; Ubiquitin/metabolism ; Ubiquitin Thiolesterase/chemistry ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin Thiolesterase/physiology
Chemical Substances	BAP1 protein, human ; Tumor Suppressor Proteins ; Ubiquitin ; Ubiquitin Thiolesterase (EC 3.4.19.12)
Language	English
Publishing date	2008-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-08-0365
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Article: Refolding of substrates bound to small Hsps relies on a disaggregation reaction mediated most efficiently by ClpB/DnaK.

Mogk, Axel / Schlieker, Christian / Friedrich, Kenneth L / Schönfeld, Hans-Joachim / Vierling, Elizabeth / Bukau, Bernd

The Journal of biological chemistry

2003 Volume 278, Issue 33, Page(s) 31033–31042

Abstract: Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that bind denatured proteins in vitro, thereby facilitating their subsequent refolding by ATP-dependent chaperones. The mechanistic basis of this refolding process is poorly defined. ... ...

Abstract	Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that bind denatured proteins in vitro, thereby facilitating their subsequent refolding by ATP-dependent chaperones. The mechanistic basis of this refolding process is poorly defined. We demonstrate that substrates complexed to sHsps from various sources are not released spontaneously. Dissociation and refolding of sHsp bound substrates relies on a disaggregation reaction mediated by the DnaK system, or, more efficiently, by ClpB/DnaK. While the DnaK system alone works for small, soluble sHsp/substrate complexes, ClpB/DnaK-mediated protein refolding is fastest for large, insoluble protein aggregates with incorporated sHsps. Such conditions reflect the situation in vivo, where sHsps are usually associated with insoluble proteins during heat stress. We therefore propose that sHsp function in cellular protein quality control is to promote rapid resolubilization of aggregated proteins, formed upon severe heat stress, by DnaK or ClpB/DnaK.
MeSH term(s)	Animals ; Endopeptidase Clp ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/metabolism ; HSP70 Heat-Shock Proteins/chemistry ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/chemistry ; Heat-Shock Proteins/metabolism ; Hot Temperature ; Malate Dehydrogenase/metabolism ; Molecular Chaperones/chemistry ; Molecular Chaperones/metabolism ; Protein Binding ; Protein Denaturation ; Protein Folding ; Solubility
Chemical Substances	Escherichia coli Proteins ; HSP70 Heat-Shock Proteins ; Heat-Shock Proteins ; Molecular Chaperones ; Malate Dehydrogenase (EC 1.1.1.37) ; Endopeptidase Clp (EC 3.4.21.92) ; dnaK protein, E coli (EC 3.6.1.-) ; ClpB protein, E coli (EC 3.6.1.3)
Language	English
Publishing date	2003-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M303587200
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Article: Solution structure and dynamics of a heat shock protein assembly probed by hydrogen exchange and mass spectrometry.

Wintrode, Patrick L / Friedrich, Kenneth L / Vierling, Elizabeth / Smith, Jean B / Smith, David L

Biochemistry

2003 Volume 42, Issue 36, Page(s) 10667–10673

Abstract: The solution conformation and dynamics of the 16.9 kDa small heat shock protein from wheat have been studied using a combination of hydrogen/deuterium exchange, proteolytic digestion, and mass spectrometry. At room temperature, HSP16.9 exists as a ... ...

Abstract	The solution conformation and dynamics of the 16.9 kDa small heat shock protein from wheat have been studied using a combination of hydrogen/deuterium exchange, proteolytic digestion, and mass spectrometry. At room temperature, HSP16.9 exists as a dodecameric assembly. Regions of HSP16.9 that form extensive and essential intersubunit contacts in the assembly, including residues 1-40 and 131-151, show little or no protection against hydrogen/deuterium exchange after incubation in D(2)O for 5 s. The high levels of hydrogen/deuterium exchange indicate that these regions have experienced large conformational fluctuations in solution, breaking intersubunit contacts and exposing buried amide hydrogens to solvent. When HSP16.9 is pulse labeled for 10 ms, residues 1-40 and 131-151 are substantially more protected than they are after 5 s. Thus, the breaking of intersubunit contacts occurs on a time scale between 10 milliseconds and 5 s. At 42 degrees C, HSP16.9 exists in a suboligomeric form. When the intrinsic temperature dependence of hydrogen/deuterium exchange is taken into account, exchange patterns at 25 and 42 degrees C are identical within experimental error, suggesting that the conformation of individual HSP16.9 subunits is the same in both the dodecameric and subdodecameric forms. Significant protection is seen in regions that form the dimeric interface, suggesting that the stable suboligomeric form is a dimer. Taken together, these results suggest that heat activation of HSP16.9 occurs by shifting the dodecamer <--> dimer equilibrium in favor of free dimers. The conformation of the dimers themselves does not appear to be altered with an increase in temperature.
MeSH term(s)	Amino Acid Sequence ; Deuterium ; Escherichia coli/metabolism ; Heat-Shock Proteins/chemistry ; Heat-Shock Proteins/genetics ; Hydrogen/chemistry ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Molecular Weight ; Peptide Fragments/analysis ; Peptide Fragments/chemistry ; Plant Proteins ; Protein Structure, Secondary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Solutions ; Spectrometry, Mass, Electrospray Ionization/methods ; Triticum/chemistry
Chemical Substances	HSP16.9 protein, Triticum aestivum ; Heat-Shock Proteins ; Peptide Fragments ; Plant Proteins ; Recombinant Proteins ; Solutions ; Hydrogen (7YNJ3PO35Z) ; Deuterium (AR09D82C7G)
Language	English
Publishing date	2003-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi034117m
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Article: The N-terminal arm of small heat shock proteins is important for both chaperone activity and substrate specificity.

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Article: The N-terminal Arm of Small Heat Shock Proteins Is Important for Both Chaperone Activity and Substrate Specificity

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Article: The ubiquitin signal: assembly, recognition and termination. Symposium on ubiquitin and signaling.

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Article: Interactions between small heat shock protein subunits and substrate in small heat shock protein-substrate complexes.

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Article ; Online: BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.

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Article: Refolding of substrates bound to small Hsps relies on a disaggregation reaction mediated most efficiently by ClpB/DnaK.

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Article: Solution structure and dynamics of a heat shock protein assembly probed by hydrogen exchange and mass spectrometry.

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