title: Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography.
abstract: Huntington disease, a neurodegenerative disorder characterized by functional deficits and loss of striatal neurons, is linked to an expanded and unstable CAG trinucleotide repeat in the huntingtin gene (HTT). This DNA sequence translates to a polyglutamine repeat in the protein product, leading to mutant huntingtin (mHTT) protein aggregation. The aggregation of mHTT is inhibited in vitro and in vivo by the TCP-1 ring complex (TRiC) chaperonin. Recently, a novel complex comprised of a single type of TRiC subunit has been reported to inhibit mHTT aggregation. Specifically, the purified CCT5 homo-oligomer complex, when compared with TRiC, has a similar structure, ATP use, and substrate refolding activity, and, importantly, it also inhibits mHTT aggregation. Using an aggregation suppression assay and cryoelectron tomography coupled with a novel computational classification method, we uncover the interactions between the synthetic CCT5 complex (∼ 1 MDa) and aggregates of mutant huntingtin exon 1 containing 46 glutamines (mHTTQ46-Ex1). We find that, in a similar fashion to TRiC, synthetic CCT5 complex caps mHTT fibrils at their tips and encapsulates mHTT oligomers, providing a structural description of the inhibition of mHTTQ46-Ex1 by CCT5 complex and a shared mechanism of mHTT inhibition between TRiC chaperonin and the CCT5 complex: cap and contain.
authors.affiliation: From the National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Darrow
authors.affiliation: the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and.
authors.forename: Oksana A
authors.initials: OA
authors.lastname: Sergeeva
authors.affiliation: the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Isas
authors.affiliation: From the National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jesús G
authors.initials: JG
authors.lastname: Galaz-Montoya
authors.affiliation: the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: King
authors.affiliation: the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.affiliation: From the National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Schmid
authors.affiliation: From the National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, wah@bcm.edu.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
mesh_terms: D056404:Chaperonin Containing TCP-1 / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D055032:Electron Microscope Tomography; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure
chemical_list: C533301:CCT5 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates; D011994:Recombinant Proteins; D056404:Chaperonin Containing TCP-1
keywords: CCT5 complex; Huntington disease; chaperonin; cryoelectron microscopy; electron tomography; protein aggregation; single-particle tomography