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

Wonki Min, Francesca Angileri, Haibin Luo, Antonino Lauria, Maruda Shanmugasundaram, Anna Maria Almerico, Francesco Cappello, Everly Conway de Macario, Igor K Lednev, Alberto J L Macario, Frank T Robb

Journal: Scientific reports 2015;4():6688

PMID: 25345891

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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.

Address: 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.; 1] 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 [2] Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.; Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Sezione di Chimica Farmaceutica e Biologica. University of Palermo, Palermo, Italy.; Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222, USA.; 1] Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC), University of Palermo, Palermo, Italy [2] Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.

DOI: 10.1038/srep06688

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MeSH Terms: Amino Acid Sequence, Archaea, Chaperonin Containing TCP-1, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Multimerization, Sequence Alignment, Thermodynamics