Biochemical Characterization of Mutants in Chaperonin Proteins CCT4 and CCT5 Associated with Hereditary Sensory Neuropathy

Sergeeva, Oksana A.; Tran, Meme T.; Haase-Pettingell, Cameron; King, Jonathan

doi:10.1074/jbc.m114.576033

Cited by 23 publications

(40 citation statements)

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“…Confirming the previous fibril formation and aggregation observations with a new mHTT construct further solidifies these findings. Moreover, the synthetic chaperonin-like CCT5 complex, which has been shown recently to also inhibit mHTT aggregation (24), was structurally characterized to provide information on its mechanism of interaction with mHTT. As shown previously, it is possible to overexpress the CCT5 subunit in bacteria, producing the CCT5 complex (23,24).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the synthetic chaperonin-like CCT5 complex, which has been shown recently to also inhibit mHTT aggregation (24), was structurally characterized to provide information on its mechanism of interaction with mHTT. As shown previously, it is possible to overexpress the CCT5 subunit in bacteria, producing the CCT5 complex (23,24). It is intriguing to raise the question of whether CCT5, as a homooligomer complex, is native to mammalian cells, which awaits future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…CCT5 Complex Purification-The human CCT5 construct was isolated as described previously (23), with a few modifications (24). Briefly, BL21(DE3)RIL Escherichia coli cells expressing human CCT5 with a His tag were lysed via French press.…”

Section: Methodsmentioning

confidence: 99%

“…In short, the CCT5 complex looks and acts similarly to TRiC chaperonin. In addition, it has been reported recently that the CCT5 complex inhibits mHTT aggregation (24), leading us to question whether the CCT5 complex also utilizes the cap and contain structural mechanisms to inhibit mHTT aggregation.…”

Section: Huntington Disease a Neurodegenerative Disorder Characterizmentioning

confidence: 99%

See 3 more Smart Citations

Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography

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Sergeeva

Isas

et al. 2015

Journal of Biological Chemistry

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Background: Huntington disease patients show an accumulation of oligomers and fibrillar species of mutant huntingtin (mHTT). Results: Cryoelectron tomography and subvolume averaging visualizes heterogeneous mHTT oligomeric species inside the chaperonin-like CCT5 cavity. Conclusion:The structural basis of mHTT aggregation inhibition by CCT5 is through capping of fibrils and encapsulation of oligomers. Significance: These structural mechanisms inspire the development of new strategies for inhibiting mHTT aggregation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Huntington Disease a Neurodegenerative Disorder Characterizmentioning

confidence: 99%

See 2 more Smart Citations

Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography

Darrow

Sergeeva

Isas

et al. 2015

Journal of Biological Chemistry

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“…In conclusion, the use of the archaeal chaperonin provided information that reflects the anomalies of the human mutant CCT5, which has been studied in vitro (Sergeeva et al, 2014). In a pioneering study, the human CCT4, and CCT5 subunits have been shown to form homohexadecamer complexes after expression of the subunits in E. coli (Sergeeva et al, 2013).…”

Section: The Thermosome Of Pyrococcus Furiosusmentioning

confidence: 99%

Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts

Macario

Robb

Macario

2017

Front. Mol. Biosci.

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All archaea have a chaperonin of Group II (thermosome) in their cytoplasm and some have also a chaperonin of Group I (GroEL; Cpn60; Hsp60). Conversely, all bacteria have GroEL, some in various copies, but only a few have, in addition, a chaperonin (tentatively designated Group III chaperonin) very similar to that occurring in all archaea, i.e., the thermosome subunit, and in the cytosol of eukaryotic cells, named CCT. Thus, nature offers a range of prokaryotic organisms that are potentially useful as experimental models to study the human CCT and its abnormalities. This is important because many diseases, the chaperonopathies, have been identified in which abnormal chaperones, including mutant CCT, are determinant etiologic-pathogenic factors and, therefore, research is needed to elucidate their pathologic features at the molecular level. Such research should lead to the clarification of the molecular mechanisms underlying the pathologic lesions observed in the tissues and organs of patients with chaperonopathies. Information on these key issues is necessary to make progress in diagnosis and treatment. Some of the archaeal organisms as well as some of the bacterial models suitable for studying molecular aspects pertinent to human mutant chaperones are discussed here, focusing on CCT. Results obtained with the archaeon Pyrococcus furiosus model to investigate the impact of a pathogenic CCT5 mutation on molecular properties and chaperoning functions are reviewed. The pathogenic mutation examined weakens the ability of the chaperonin subunit to form stable hexadecamers and as a consequence, the chaperoning functions of the complex are impaired. The future prospect is to find means for stabilizing the hexadecamer, which should lead to a recovering of chaperone function and the improving of lesions and clinical condition.

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Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies

Macario

2019

The Journal of Pathology

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Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation.The canonical functions of chaperones pertain to the maintenance of protein homeostasis, in essence protein-quality control; for example: assisting in the correct folding of nascent polypeptides, ushering polypeptides to their place of residence including through membranes, helping partially denatured

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Biochemical Characterization of Mutants in Chaperonin Proteins CCT4 and CCT5 Associated with Hereditary Sensory Neuropathy

Cited by 23 publications

References 40 publications

Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography

Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography

Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts

Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies

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