MitCHAP-60 and Hereditary Spastic Paraplegia SPG-13 Arise from an Inactive hsp60 Chaperonin that Fails to Fold the ATP Synthase β-Subunit

Wang, Jinliang; Enriquez, Adrian S.; Li, Jihui; Rodrı́guez, Alejandro; Holguin, Bianka A.; Salzen, Daniel Von; Bhatt, Jay M.; Bernal, Ricardo A.

doi:10.1038/s41598-019-48762-5

Cited by 15 publications

(19 citation statements)

References 59 publications

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“…Structural studies on both mutants have highlighted the strong effect nucleotide binding has on the mutant mtHsp60 proteins. Electron microscopy and dynamic light scattering studies showed that mtHsp60 harboring either the D29G or V98I mutation dissociated into monomers upon the addition of nucleotide (ATP and ADP had the same effect on complex disruption) (Wang et al, 2019). The nucleotide free (APO) state was able to oligomerize and was stable under experimental conditions suggesting that the mutations have deleterious structural effects mainly during nucleotide binding and or hydrolysis.…”

Section: Chaperonopathies and The Role Of Mthsp60 In Diseasementioning

confidence: 99%

“…MtHsp60 can alternate between single and double heptameric ring conformations upon nucleotide binding and following hydrolysis ( Viitanen et al, 1992 , 1998 ; Nielsen and Cowan, 1998 ; Nielsen et al, 1999 ; Levy-Rimler et al, 2001 ; Nisemblat et al, 2014 , 2015 ; Vilasi et al, 2014 , 2018 ; Enriquez et al, 2017 ; Jebara et al, 2017 ; Bhatt et al, 2018 ; Wang et al, 2019 ; Gomez-Llorente et al, 2020 ). Furthermore, the structure of the ATP bound conformation has recently been solved, both by crystallography and electron microscopy.…”

Section: The Chaperonin Protein Folding Cyclementioning

confidence: 99%

“…In these structures, mtHsp60 adopts a symmetric “American football” like conformation, with two rings sitting against each other via contacts in their equatorial domains, while both rings are capped by one heptameric ring of Hsp10 positioned directly on the apical domain ( Nisemblat et al, 2014 , 2015 ; Wang et al, 2019 ; Gomez-Llorente et al, 2020 ). Recently, ADP bound mtHsp60 has been shown to separate into single rings capped with an Hsp10 heptamer ( Wang et al, 2019 ). Additionally, nucleotide free mtHsp60 has been shown to form single ring toroidal complexes when reconstituted in vitro ( Viitanen et al, 1998 ).…”

Section: The Chaperonin Protein Folding Cyclementioning

confidence: 99%

“…It is hypothesized that these loss-of-function mutants pose a high risk of cell damage due to a higher susceptibility to protein aggregate formation. Additionally, there is an inability to fold key proteins involved in the energetic pathways found in mitochondria, the latter resulting in energy deprived cells (Parnas et al, 2009;Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Rodrı́guez

Salzen

Holguin

et al. 2020

Front. Mol. Biosci.

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Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. In humans, HSPD1 encodes the mitochondrial Heat Shock Protein 60 (mtHsp60) chaperonin, which carries out essential protein folding reactions that help maintain mitochondrial and cellular homeostasis. It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron cells. Carriers of these mutations usually develop neuropathies and paraplegias at different stages of their lives mainly characterized by leg stiffness and weakness as well as degeneration of spinal cord nerves. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. Although the complete protein folding mechanism of mtHsp60 is not well understood, recent work suggests that several of these mutations act by destabilizing the oligomeric stability of mtHsp60. Here, we discuss recent studies that highlight key aspects of the mtHsp60 mechanism with a focus on some of the known disease-causing point mutations, D29G and V98I, and their effect on the protein folding reaction cycle.

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Section: Chaperonopathies and The Role Of Mthsp60 In Diseasementioning

confidence: 99%

Section: The Chaperonin Protein Folding Cyclementioning

confidence: 99%

Section: The Chaperonin Protein Folding Cyclementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Rodrı́guez

Salzen

Holguin

et al. 2020

Front. Mol. Biosci.

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“…b Because of the use of T4 as the transducing phage, the expected linkage between the Tet R and Cam R genes is higher than that reported by Hansen et al (2002). the HSP60 chaperone complex (Wang et al 2019). These disease-associated amino acids are located in close proximity to each other and the ATP-binding domain, yet are not directly in contact with the bound ATP (Fig.…”

Section: Discussionmentioning

confidence: 98%

A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy

Cömert

Brick

Áng

et al. 2020

Cold Spring Harb Mol Case Stud

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Standardization of the use of next-generation sequencing for the diagnosis of rare neurological disorders has made it possible to detect potential disease-causing genetic variations, including de novo variants. However, the lack of a clear pathogenic relevance of gene variants poses a critical limitation for translating this genetic information into clinical practice, increasing the necessity to perform functional assays. Genetic screening is currently recommended in the guidelines for diagnosis of hypomyelinating leukodystrophies (HLDs). HLDs represent a group of rare heterogeneous disorders that interfere with the myelination of the neurons in the central nervous system. One of the HLD-related genes is HSPD1, encoding the mitochondrial chaperone heat shock protein 60 (HSP60), which functions as folding machinery for the mitochondrial proteins imported into the mitochondrial matrix space. Disease-causing HSPD1 variants have been associated with an autosomal recessive form of fatal hypomyelinating leukodystrophy (HLD4, MitCHAP60 disease; MIM #612233) and an autosomal dominant form of spastic paraplegia, type 13 (SPG13; MIM #605280). In 2018, a de novo HSPD1 variant was reported in a patient with HLD. Here, we present another case carrying the same heterozygous de novo variation in the HSPD1 gene (c.139T > G, p.Leu47Val) associated with an HLD phenotype. Our molecular studies show that the variant HSP60 protein is stably present in the patient's fibroblasts, and functional assays demonstrate that the variant protein lacks in vivo function, thus confirming its disease association. We conclude that de novo variations of the HSPD1 gene should be considered as potentially disease-causing in the diagnosis and pathogenesis of the HLDs.

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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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MitCHAP-60 and Hereditary Spastic Paraplegia SPG-13 Arise from an Inactive hsp60 Chaperonin that Fails to Fold the ATP Synthase β-Subunit

Cited by 15 publications

References 59 publications

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy

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

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