Mechanistic Insight into the Suppression of Polyglutamine Aggregation by SRCP1. ACS Chem Biol 2023 Mar 17;18(3):549-560
Date
02/16/2023Pubmed ID
36791332Pubmed Central ID
PMC10023506DOI
10.1021/acschembio.2c00893Scopus ID
2-s2.0-85148304370 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Protein aggregation is a hallmark of the polyglutamine diseases. One potential treatment for these diseases is suppression of polyglutamine aggregation. Previous work identified the cellular slime mold Dictyostelium discoideum as being naturally resistant to polyglutamine aggregation. Further work identified serine-rich chaperone protein 1 (SRCP1) as a protein that is both necessary in Dictyostelium and sufficient in human cells to suppress polyglutamine aggregation. Therefore, understanding how SRCP1 suppresses aggregation may be useful for developing therapeutics for the polyglutamine diseases. Here we utilized a de novo protein modeling approach to generate predictions of SRCP1's structure. Using our best-fit model, we generated mutants that were predicted to alter the stability of SRCP1 and tested these mutants' stability in cells. Using these data, we identified top models of SRCP1's structure that are consistent with the C-terminal region of SRCP1 forming a β-hairpin with a highly dynamic N-terminal region. We next generated a series of peptides that mimic the predicted β-hairpin and validated that they inhibit aggregation of a polyglutamine-expanded mutant huntingtin exon 1 fragment in vitro. To further assess mechanistic details of how SRCP1 inhibits polyglutamine aggregation, we utilized biochemical assays to determine that SRCP1 inhibits secondary nucleation in a manner dependent upon the regions flanking the polyglutamine tract. Finally, to determine if SRCP1 more could generally suppress protein aggregation, we confirmed that it was sufficient to inhibit aggregation of polyglutamine-expanded ataxin-3. Together these studies provide details into the structural and mechanistic basis of the inhibition of protein aggregation by SRCP1.
Author List
Haver HN, Wedemeyer M, Butcher E, Peterson FC, Volkman BF, Scaglione KMAuthors
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
DictyosteliumHumans
Huntingtin Protein
Molecular Chaperones
Peptides
Protein Aggregates
Serine
