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J Biol Chem, Vol. 274, Issue 6, 3363-3371, February 5, 1999
From the Department of Cell Biology, Harvard Medical School,
Boston, Massachusetts 02115
Knowledge about the sizes of peptides generated
by proteasomes during protein degradation is essential to fully
understand their degradative mechanisms and the subsequent steps in
protein turnover and generation of major histocompatibility complex
class I antigenic peptides. We demonstrate here that 26 S and activated 20 S proteasomes from rabbit muscle degrade denatured, nonubiquitinated proteins in a highly processive fashion but generate different patterns
of peptides (despite their containing identical proteolytic sites).
With both enzymes, products range in length from 3 to 22 residues, and
their abundance decreases with increasing length according to a
log-normal distribution. Less than 15% of the products are the length
of class I presented peptides (8 or 9 residues), and two-thirds are too
short to function in antigen presentation. Surprisingly, these
mammalian proteasomes, which contain two "chymotryptic," two
"tryptic," and two "post-acidic" active sites, generate
peptides with a similar size distribution as do archaeal 20 S
proteasomes, which have 14 identical sites. Furthermore, inactivation
of the "tryptic" sites altered the peptides produced without
significantly affecting their size distribution. Therefore, this
distribution is not determined by the number, specificity, or
arrangement of the active sites (as proposed by the "molecular
ruler" model); instead, we propose that proteolysis continues
until products are small enough to diffuse out of the proteasomes.
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