Folds & domains: The next level of organization

In protein structures helices and strands may be connected to each other and combined in many ways. However, from known protein three-dimensional structures, we have learned that there is only a limited number of ways by which secondary structure elements are combined in proteins. These different ways are called fold (or Topology according to CATH classification). Here we will examine some typical examples of connectivity and packing of secondary structure elements within 3D structures. After this we will look closer on the concept of domains and how domains are classified. This type of analysis significantly simplifies the comparison of protein structure, reveals similarities and differences between structures and opens the way for structure classification.

The helix bundle domain
One of the simplest protein structural motifs is a helix bundle (images below show two different bundles). Helix bundles are very common in protein structures and are very often found as separate domains within larger, multi-domain proteins. On the left image is an example showing the crystal structure of a
De Novo designed protein (PDB id 1MFT). In this case the helices are connected to each other by short loops and packed in a way that allows them to form a hydrophobic core in the middle of the bundle. On the right is a solution structure of headpiece domain of chicken villin (PDB code 1QQV). Here the arrangement of the helices is very different and the loops are much longer.
Clicking the images will take you to the RCSB PDB 3D-viewer, where you can rotate the structures to get a better impression of how they are built:

Connecting strands and helices: The Rossmann fold
The strands within parallel and anti-parallel β-sheets (
discussed earlier) may be connected by different structural elements like loops, helices or coil regions (without defined secondary structure). Probably the simplest and most common connectivity is made by loops, like in a hairpin described earlier. The example below shows the Rossmann fold, after Michael G. Rossmann, a protein crystallographer who solved the structure of lactate dehydrogenase, the first structure that contained this domain type. It is also the only protein fold named after the person who discovered it. Rossmann fold domains are involved in binding nucleotide cofactors of enzymatic reactions like NADH, FAD, FMN, etc. A discussion of details and the history of the Rossmann fold can be found on Proteopedia.

schematic Rossmann fold
Rossmann type of fold

The Rossmann fold domain
In the image on the left a schematic representation of the Rossmann fold is shown, which consists of a parallel 6-stranded β-sheet flanked by α-helices. The image on the right shows the 6-stranded parallel Rossmann fold β-sheet of liver alcohol dehydrogenase. The NADH molecule bound to the enzyme is shown as a sticks model (PDB ID 2OHX). Notice the central parallel β-sheet (in yellow) flanked by α-helices on both sides of its plane. The helices which should be on top of the sheet are removed here for clarity.

The TIM barrel fold domain
In the fold known as the TIM barrel fold (the name is based on the first protein where it was found,
Triose phosphate IsoMerase), one of the most widespread type of protein folds, the strands of the β-sheet are parallel. Details of the mechanism and function of this protein can be found on the respective Proteopedia page. The connectivity between the strands is again made by α-helices:

TIM barrel domain

Other examples of connectivity/fold
Examples of connectivity in anti-parallel sheets are shown below. In the first two hairpins are connected to each other, while in the second example there is the so-called Greek-key motif type of connectivity:

anti-parallel beta-sheet

In the following image the protein plastocyanin (PDB code 1bxu) is shown, which predominantly contains β–strands and coiled regions is shown. Only a short helical turn can be found in this protein.

Plastocyanin anti-parallel beta-sheet

These are just some examples of protein domains with different type of fold and different connectivity between secondary structure elements. There is of course a much large number of other types of structural motifs and domains. We get better aquatinted with them when we work with some projects, for example homology modelling.
In the following section we will continue this discussion and look closer on how domains are defined and classified.