The Sacsin Repeating Region (SRR): A Novel Hsp90-Related Supra-Domain Associated with Neurodegeneration

John F. Anderson, Efrain Siller, Jose M. Barral

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    Protein supra-domains are defined as recurring arrangements of two or three domains present adjacent to each other along a polypeptide chain. Such combinations have novel functions beyond those of the individual partner domains that compose them, which can exist in isolation. Here, we describe a new type of large supra-domain (~360 residues) in which one of the component partners (~200 residues) appears to be incapable of existing in a context other than immediately adjacent to the C-terminus of the well-characterized Hsp90-like ATPase domain. We found that this supra-domain has a broad phylogenetic distribution, with examples in Archaea, Bacteria, and Eukarya. There is strong selective pressure for this arrangement to occur as part of repeated regions of unprecedented length. We identified multiple strategies of convergent evolution to attain such configurations. In humans, this supra-domain is present in triplicate at the N-terminus of the protein sacsin (4579 residues), mutated in the neurodegenerative disorder known as spastic ataxia of Charlevoix-Saguenay, and thus, we termed it "sacsin repeating region" (SRR). Biochemical characterization demonstrated that SRRs possess ATPase activity, which appears to be a requirement for sacsin function, as a disease-causing mutation leads to an alternate conformation completely incapable of hydrolyzing ATP. We also found evidence of a convergent evolutionary strategy to place SRRs in proteins containing C-terminal J domains, which we demonstrated here to be capable of stimulating the intrinsic ATPase activity of Hsp70. Our sequence and biochemical analyses indicate that SRRs necessitate nucleotide hydrolysis for their function, provided by the common Hsp90 ATPase domain, which, when coupled to the unique adjacent sequence, may give rise to a novel activity related to protein quality control.

    Original languageEnglish (US)
    Pages (from-to)665-674
    Number of pages10
    JournalJournal of Molecular Biology
    Volume400
    Issue number4
    DOIs
    StatePublished - Jul 2010

    Fingerprint

    Adenosine Triphosphatases
    Archaea
    Protein C
    Eukaryota
    Neurodegenerative Diseases
    Quality Control
    Sequence Analysis
    Proteins
    Hydrolysis
    Nucleotides
    Adenosine Triphosphate
    Bacteria
    Peptides
    Mutation

    Keywords

    • Ataxia
    • Molecular chaperone
    • Protein folding
    • Protein misfolding
    • Protein supradomain

    ASJC Scopus subject areas

    • Molecular Biology

    Cite this

    The Sacsin Repeating Region (SRR) : A Novel Hsp90-Related Supra-Domain Associated with Neurodegeneration. / Anderson, John F.; Siller, Efrain; Barral, Jose M.

    In: Journal of Molecular Biology, Vol. 400, No. 4, 07.2010, p. 665-674.

    Research output: Contribution to journalArticle

    Anderson, John F. ; Siller, Efrain ; Barral, Jose M. / The Sacsin Repeating Region (SRR) : A Novel Hsp90-Related Supra-Domain Associated with Neurodegeneration. In: Journal of Molecular Biology. 2010 ; Vol. 400, No. 4. pp. 665-674.
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