Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins.
Long glutamine sequences (polyQ) occur in many cell proteins, and several neurodegenerative diseases result from expansion of these sequences. PolyQ-containing proteins are degraded by proteasomes, whose three active sites prefer to cleave after hydrophobic, basic, or acidic residues. We tested whether these particles can digest a polyQ chain. Eukaryotic 26S and 20S proteasomes failed to cut within stretches of 9-29Q residues in peptides. While digesting a myoglobin Q(35) fusion protein, the proteasomes spared the polyQ sequence. In contrast, archaeal proteasomes, whose 14 active sites are less specific, rapidly digested such polyQ repeats. Therefore, when degrading polyQ proteins, eukaryotic proteasomes must release aggregation-prone polyQ-containing fragments for further hydrolysis by unidentified peptidases. In polyQ diseases, such polyQ sequences (38-300Qs) exceed the lengths of normal proteasome products (2-25 residues). Occasional failure of these long undegradable sequences to exit may interfere with proteasome function and help explain why longer polyQ expansions promote early disease onset.
Venkatraman
Prasanna
P
Department of Cell Biology, 240 Longwood Avenue, Harvard Medical School, Boston, MA 02115, USA.
Wetzel
Ronald
R
Tanaka
Motomasa
M
Nukina
Nobuyuki
N
Goldberg
Alfred L
AL
D000818:Animals; D019843:Archaeal Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid
D019843:Archaeal Proteins; D005656:Fungal Proteins; D009097:Multienzyme Complexes; D009211:Myoglobin; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; C097188:polyglutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex