Opening Image: Human UDP-galactose epimerase, a homodimer.

Outline

1. Complementarity
2. Protein-Protein Interactions
3. Case Study

Complementarity

The basis for molecular recognition between two identical protein subunits is that the interfaces must be precisely complementary. This complementarity comprises three features:

1. Hydrogen bond complementarity. Any hydrogen bond donor on one subunit must find a hydrogen bond acceptor on the opposite.
2. Ionic complementarity. All possible salt bridges must be made. If there is a minus charge on one subunit, there must be a positive charge opposite on the other side.
3. Steric or shape complementarity. The two surfaces at the interface between the subunits must fit very snugly. The hydrophobic cores of each subunit often merge at the interface to form a common hydrophobic core. There are two criteria for packing: avoidance of steric overlap and complete filling of available space. Separating a pair of atoms even 1 Å will eliminate the van der Waals energy. Directed mutations in which a small amino acid is replaced by a bulky one can completely eliminate binding.

Protein-Protein Interactions

Basically, protein-protein interactions come in four flavors:

1. Hydrophobic interfaces: often seen in smaller proteins, the contact surfaces can be entirely nonpolar. For homodimeric proteins, the hydrophobic contact faces are relatively flat and make up a comparatively small fraction of the total surface area. The absence of hydrogen bonding groups at the interface accounts for the absence of hydrogen bonds between the subunits as well as the absence of bound water molecules at interface. The interaction energy has two components, the hydrophobic effect and van der Waals interactions.
2. Hydrophobic interfaces with one or more water molecules sandwiched between the subunits.
3. Hydrophobic interfaces with salt bridges around the perimeter of the subunit interface.
4. Hydrophobic interfaces with hydrogen bonds between the two complementary interfaces.

Case Study: UDP-galactose Epimerase

A homodimer with a flat hydrophobic interface

UDP-galactose epimerase (GALE) catalyzes a key step in galactose metabolism. Only a few GALE mutations have been reported. They are of the missense type and retain some activity. It is believed that mutations causing large losses in activity are lethal during embryonic development. The dimer shows a loss of 1,816 Ų of solvent-accessible surface area upon complex formation.

Surface model of GALE. The two substrates, UDP-galactose and NADH, are shown in spacefill.

Surface model of chain B.

Toggle chain B as a cartoon. Return to the surface model of GALE in order to view the interface between subunits.