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

• Published in: Scientific reports Vol. 4; no. 1; p. 6688
• Main Authors: Min, Wonki, Angileri, Francesca, Luo, Haibin, Lauria, Antonino, Shanmugasundaram, Maruda, Almerico, Anna Maria, Cappello, Francesco, de Macario, Everly Conway, Lednev, Igor K., Macario, Alberto J. L., Robb, Frank T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-10-2014; Nature Publishing Group
• Subjects: 45; 631/45/612/1981; 692/53; 82; 82/80; Adenosine triphosphatase; Amino Acid Sequence; Archaea - genetics; Chaperonin Containing TCP-1 - chemistry; Chaperonin Containing TCP-1 - genetics; Chaperonins; Homeostasis; Humanities and Social Sciences; Humans; Models, Molecular; Molecular Sequence Data; multidisciplinary; Mutation; Neuropathy; Point mutation; Protein Conformation; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Science; Sequence Alignment; Thermodynamics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep06688

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.