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A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model.

Min W, Angileri F, Luo H, Lauria A, Shanmugasundaram M, Almerico AM, Cappello F, de Macario EC, Lednev IK, Macario AJ, Robb FT - Sci Rep (2014)

Bottom Line: These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog.The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective.Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and Institute of Marine and Environmental Technology (IMET); Columbus Center, Baltimore, MD 21201, USA.

ABSTRACT
Chaperonins mediate protein folding in a cavity formed by multisubunit rings. The human CCT has eight non-identical subunits and the His147Arg mutation in one subunit, CCT5, causes neuropathy. Knowledge is scarce on the impact of this and other mutations upon the chaperone's structure and functions. To make progress, experimental models must be developed. We used an archaeal mutant homolog and demonstrated that the His147Arg mutant has impaired oligomeric assembly, ATPase activity, and defective protein homeostasis functions. These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog. The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective. Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.

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Related in: MedlinePlus

Dispersion of amyloid fibrils by archaeal PfCD (top strip of panels), partial dispersion by I138H (middle strip of panels) and lack of dispersion by I138R (bottom strip of panels).
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f6: Dispersion of amyloid fibrils by archaeal PfCD (top strip of panels), partial dispersion by I138H (middle strip of panels) and lack of dispersion by I138R (bottom strip of panels).

Mentions: In Fig. 6, the ability of the archaeal Cpn60 to deconstruct and disperse amyloid fibrils under mild conditions, a system that has been described in detail elsewhere26, is confirmed. The top panel shows the activity of the PfCD Cpn60 to disrupt fibrils completely in 30 min. The activity of the I138H mutant is similar to PfCD (middle panel), whereas the I138R mutant is defective, and the fibrils are intact at 60 min (bottom panel).


A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model.

Min W, Angileri F, Luo H, Lauria A, Shanmugasundaram M, Almerico AM, Cappello F, de Macario EC, Lednev IK, Macario AJ, Robb FT - Sci Rep (2014)

Dispersion of amyloid fibrils by archaeal PfCD (top strip of panels), partial dispersion by I138H (middle strip of panels) and lack of dispersion by I138R (bottom strip of panels).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209464&req=5

f6: Dispersion of amyloid fibrils by archaeal PfCD (top strip of panels), partial dispersion by I138H (middle strip of panels) and lack of dispersion by I138R (bottom strip of panels).
Mentions: In Fig. 6, the ability of the archaeal Cpn60 to deconstruct and disperse amyloid fibrils under mild conditions, a system that has been described in detail elsewhere26, is confirmed. The top panel shows the activity of the PfCD Cpn60 to disrupt fibrils completely in 30 min. The activity of the I138H mutant is similar to PfCD (middle panel), whereas the I138R mutant is defective, and the fibrils are intact at 60 min (bottom panel).

Bottom Line: These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog.The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective.Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and Institute of Marine and Environmental Technology (IMET); Columbus Center, Baltimore, MD 21201, USA.

ABSTRACT
Chaperonins mediate protein folding in a cavity formed by multisubunit rings. The human CCT has eight non-identical subunits and the His147Arg mutation in one subunit, CCT5, causes neuropathy. Knowledge is scarce on the impact of this and other mutations upon the chaperone's structure and functions. To make progress, experimental models must be developed. We used an archaeal mutant homolog and demonstrated that the His147Arg mutant has impaired oligomeric assembly, ATPase activity, and defective protein homeostasis functions. These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog. The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective. Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.

Show MeSH
Related in: MedlinePlus