Principles of Protein Structure - G. Schulz 1982

Mechanisms of polypeptide chain folding and association
Aggregates of globular proteins
Subunit contacts in dehydrogenases

The 222-tetramer requires The formation of only two out of three possible types of contacts. Let us examine the types of contacts that can form in a symmetric oligomer, using four dehydrogenases of known Structure as an example. s-Malate and Alcohol dehydrogenases are dimers of identical subunits with point group 2, whereas lactate and glyceraldehyde-3-phosphate dehydrogenases are tetramers of identical subunits with point group 222 (Fig. 5.16, a). Dimers form only a single type of contact near the 2-fold rotation axis (Fig. 5.18, a). Tetramers possess Three types of contacts, one at the intersection with each 2-fold axis (Fig. 5.18, b). Notably, only two of the three contacts are necessary to stabilize the tetramer.

The contacts of a 222-tetramer can be represented by a triangular diagram. These tetrameric contacts can be conceptually described by the tetrahedron shown in Fig. 5.18, b, as well as by the two-dimensional graph in Fig. 5.18, c. A color code is used to identify the subunits, and the 2-fold rotation axes are designated as P, Q, and R. The "red" subunit is taken as the reference; it forms contacts with the "blue", "yellow", and "green" subunits, which intersect at the P, Q, and R axes, respectively. As seen in Fig. 5.18, d, the two-dimensional graph is convenient for counting interactions between the residues of the "red" subunit and those of the other subunits.

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Fig. 5.18. Oligomeric Enzymes—dehydrogenases. a — diagram of a symmetric dimer, such as Alcohol dehydrogenase; there is only a single type of interface. The contacting surfaces are complementary (lock-and-key model [44]). b — a 222-Symmetry tetramer represented as a tetrahedron. The three 2-fold rotation axes P, Q, and R are indicated. Each subunit is represented by a triangle, and each contact between subunits by an edge; c — a planar representation of the tetrahedron and inter-subunit contacts; d — use of the planar representation to identify atomic contacts between Lactate dehydrogenase subunits [264]; e — evolutionary tree of dehydrogenases constructed based on the analysis of inter-subunit contacts [264]. ADH — alcohol dehydrogenase, GAFDH — glyceraldehyde-3-phosphate dehydrogenase, LDH — lactate dehydrogenase, MDH — s-malate dehydrogenase.

Contacts reveal evolutionary relationships. Rossmann et al. [264, 265] demonstrated that the four dehydrogenases are evolutionarily related and that comparing inter-subunit contacts allows certain details of this relationship to be uncovered. These contacts can be compared because all four dehydrogenases share the same nucleotide-binding domain (Fig. 5.17, b), which makes up approximately half of the subunit. Such a domain can be used as a baseline. Lactate and s-malate dehydrogenases feature nearly identical chain folding, indicating that these Proteins are closely related. Glyceraldehyde-3-phosphate, lactate, and s-malate dehydrogenases form a Q-axis contact (shown in Fig. 5.18, d). Accordingly, the "red"–"yellow" dimer must have been well conserved during Introduction/18.html">Protein Evolution. As for the P- and R-axis contacts of the dehydrogenases, they show no similarity whatsoever. Furthermore, there is no resemblance between the contact in alcohol dehydrogenase and any other contact*. The evolutionary relationship scheme constructed from these data is presented in Fig. 5.18, e.