MHC CLASS I MOLECULES ASSOCIATE WITH ENDOGENOUS PEPTIDES

Ribosomes are error prone during the course of rapid

synthesis of viral proteins and there is evidence that
defective ribosomal products (also known as DRiPs) are a
direct source of peptides for MHC class I molecules.

experiments in vitro. Using a similar system it was shown

that the most efficient transport occurred with peptide
substrates of 815 amino acids. Although this size is close
to the length preference of MHC class I molecule binding
sites, it suggests that some additional trimming may be
required by enzymes in the lumen of the ER. These
include an ER amino peptidase, ERAP, and enzymes such
as the TPPII complex may also contribute to trimming
the N termini of peptides for class I binding.
Recent evidence has suggested that some of the
components of the processing pathway are physically
associated in the ER (Fig. 7.9). For example:
newly synthesized MHC class I molecule2-microglobulin complexes are associated with TAP in the ER;
another MHC-encoded protein, called tapasin, forms
a bridge between the MHC class I molecule and
TAP, until peptide is associated with the class I
molecule; dissociation occurs upon transport to the
cis-Golgi.
Peptide loading involves other proteins such as calnexin,
calreticulin, and ERp57. These chaperones promote and
guide the assembly of stable MHC class I molecule2microglobulinpeptide complexes.

Q. What advantage might there be in presenting DriPs on

MHC class I molecules rather than fragments of mature viral
peptides?
A. DriP-derived peptides will be generated earlier in infection
than fragments produced by the degradation of mature viral
proteins. This allows the CTLs to recognize virus-infected cells
more quickly.

How do the peptides produced by proteasomes

traverse the ER?
The products of two genes, TAP1 and TAP2, that map
adjacent to LMP2 and LMP7 in the MHC (see Fig. 7.8),
function as a heterodimeric transporter that translocates
peptides into the lumen of the ER. TAP is a member
of the large ATP-binding cassette (ABC) family of transporters localized in the ER membrane. Microsomes from
cells lacking TAP1 or TAP2 could not take up peptide in

Assembly of endogenous peptides with MHC class I molecules

ABC
proteolysis

ABC
tapasin

peptide

proteasome
protein

rough endoplasmic
reticulum

!2microglobulin

transport
to plasma
membrane

class I
" chain
calnexin
Fig. 7.9 Proposed assembly pathway of antigenMHC class I molecule complex.
Cytoplasmic antigens are processed by proteasomes (see Fig. 7.7). Peptides are
transported by two members of the ABC superfamily of transporters, also encoded
within the MHC (TAP1 and TAP2). Antigenic peptides associate with class I heavy
chains (see Fig. 5.6) and 2-microglobulin in the ER. Molecular chaperones, such as
calnexin and calreticulin, associate with partially assembled class I complexes. The
class I molecule waiting to be loaded with peptide is engaged in a complex of
proteins. The complex includes calreticulin, a lectin-like chaperone that binds to a
sugar residue on the class I molecule. ERp57, a thiol oxido-reductase non-covalently
associates with calreticulin and is disulfide bonded to tapasin. The immunoglobulin
superfamily molecule tapasin forms a bridge between TAP and the MHC class I
molecule, and may also act as a peptide editor. An intact loading complex is
essential for efficient MHC class I association with peptide. The fully assembled class I
molecules are transported to the cell surface.

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