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Copyright 2005 by Eric Martz,
University of Massachusetts, Amherst MA USA.

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MHC Class I: Analysis of Evolutionary Conservation and Variability of the Molecular Surface

performed by the ConSurf Server).

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MHC Class I --
Major Histocompatibility Class I

is a transmembrane molecule. The domains shown here are expressed on the surfaces of most kinds of cells in vertebrates. In this example (2VAA, mouse H-2Kb), the transmembrane and cytoplasmic domains were deleted from the carboxy terminal end (ball) to enable crystallization for X-ray diffraction studies.
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MHC Class I
is crucial in immune defenses against infectious microbes. It samples peptides (8-9 amino acids in length) produced by the proteasome in the cytoplasm. Each MHC molecule presents one peptide (orange) on the surface of the cell. T lymphocytes inspect the MHC:peptide complexes. Detection of a foreign peptide signals an infection within the cell, and the T cells intervene to control the infection (possibly killing the cell). In this example, the peptide is from vesicular stomatitus virus nucleoprotein (52-59).
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The extracellular domains of MHC I (shown here)

include an alpha chain and a beta chain. The latter is termed beta-2 microglobulin. Only the alpha chain has a trans-membrane domain (deleted here at the ball). The beta chain is anchored by noncovalent binding to the alpha chain .
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Evolutionary Conservation of MHC Class I

alpha chain is shown (from the ConSurf Server):
Some amino acids have insufficient data for calculating a conservation grade. These are marked yellow . This is because only 50 sequences were aligned for calculating the conservation grades. (When 150 are used, all amino acids have sufficient data.)

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Conservation of the a chain surface where b-2 microglobulin binds to it.


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Conservation of atoms of the a chain that contact b-2 microglobulin.

Shown: a chain atoms within 4.0 of b-2 microglobulin.

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Variability of amino acids in the a chain that bind the virus peptide.

MHC Class I has more alleles than any other genetic locus. Most of the variation between alleles concentrates in the peptide-binding groove. This enables a small number of MHC Class I genes to bind a very large number of possible foreign peptides.

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CD8 Binding Site:
CD8 (not shown) is a receptor on T lymphocytes, crucial for T cell recognition of foreign peptide presented by MHC class I.

The core of the CD8 binding side on the MHC a chain is residues 214, 222-233, and 243 (spacefilled here). ConSurf shows that this binding site is conserved.
[Binding site observed in 1BQH.]

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CD8 Binding Site:
The conserved CD8 binding site is shown here again, as in the previous slide, but with the remainder of the a chain shown spacefilling in gray.


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