Page 297 - Veterinary Immunology, 10th Edition

project out of the ends. Because of this, MHC class I molecules only
VetBooks.ir bind peptides containing about nine amino acids. In order to do so,

these peptides must bulge out in the middle. Overall, however, the
antigen-binding sites on class II and class I molecules function in a

similar manner.
The processing of endogenous peptides differs from the
processing of exogenous peptides. Living cells continually break up
and recycle the proteins they produce. As a result, abnormal

proteins are removed, regulatory peptides do not accumulate, and
amino acids are recycled. As a first step, the protein must be tagged.
To do this, ubiquitin, a small protein found in all eukaryote cells,
attaches to lysine residues in target proteins. Additional ubiquitins

then attach to the protein-bound ubiquitin so that several ubiquitin
molecules are linked like beads on a string. A chain of four
ubiquitin molecules appears to be optimal for processing. These
polyubiquinated proteins are marked for destruction since they are

recognized by enzyme complexes called proteasomes.
Proteasomes are tubular molecular complexes whose function is
to degrade ubiquinated proteins. They consist of an inner channel
that contains the protease activity and two outer rings that regulate

which proteins can enter and be destroyed. Ubiquitinated proteins
bind to the outer rings, the tagged protein is unfolded, and the
ubiquitin is released and reused. The unfolded protein is inserted
into the inner channel, where it is broken into 8- to 15-amino acid

long peptides (like a meat grinder). Most of these peptide fragments
are recycled into new proteins. For about 1 in 1 million molecules,
however, the peptides are rescued from further breakup by
attachment to transporter proteins. Two transporter proteins are

used: TAP-1 and TAP-2 (TAP stands for transporter for antigen
processing). TAP-1 and TAP-2 form a heterodimer that binds
peptide fragments and transports them into endosomes. Ideally, an
8- to 10-amino acid peptide precisely fits the binding site on the

heterodimer. In this case the peptide is loaded into the TAP dimer,
carried to a newly formed MHC, and if it fits the MHC antigen-
binding site, it is transferred. Once loaded on the MHC, the MHC-
peptide complex is carried to the cell surface by its normal secretory
pathway where it is displayed for many hours.

6
A cell can express about 10 MHC-peptide complexes at any one

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