Conservation of Structural Features

What follows is some work I did in Oxford with Geoff Barton. You can read this paper by clicking here.

In all figures shown below, pairs of proteins are shown which adopt similar three-dimensional (3D) structures in the absense of any apparent sequence similarity. All structure are shown side-by-side in a superimposed orientation. Regions of the structure that are structurally equivalent are shown as arrows, ribbons or coils; structurally unconserve regions are shown as C-alpha trace. The structures are coloured from Blue-to-Red as the chain progresses from N- to C- terminus. Below eac pair of structures is the correponding structurally-based sequence alignment. Structurally equivalent regions are boxed. Those residues having equivalent values for each of the three structural features discussed are shown in pink. More details are given below.

Type B similarities refer to those pairs of protein 3D structures having structural and functional similarities (e.g. eukaryotic and viral aspartic proteinases; globins from root nodules and mammals; etc.). Type C similarities refer to those pairs of protein 3D structures having only 3D structural similarity (i.e. no sequence or functional similarity). Type B similarities are usually argued to be related by divergent evolution, wherease type C similarities are argued either way (depending on ones opinion). The figures show that structural conservation bears no relation to functional similarity; often proteins having no functional similarity have a degree of structural feature (e.g. accessibility, secondary structure, etc.) conservation comparable to, or even higher than, proteins having functional similarity.

See Russell, R.B. & Barton, G.J. (1994) J. Mol. Biol. , 244, 332-350.

Protein Core conservation

Type B similarity: Biotin operon protein (BirA; PDB code 1BIA) and HNF-3 (below) are both DNA binding domains with a common helix-turn-helix motif. Only 45.1 % of their residues can be deemed structurally equivalent.

Type C similarity: Ricin (1AAI_A) and Basic Fibroblast Growth factor (2FGF; below) have a much higher degree of structurally equivlent residues (almost 66 %). However, unlike the BirA/HNF-3 example, these two proteins have no apparent functional similarity.

Accessibility conservation

Type B similarity: malate and glucose-6-phosphate dehydrogenase (4MDH_A and 2G6P; below) have obvious functional similarity: they both bind NAD or NADP, they catalyse similar reactions, and they even have a few regions of local sequence similarity (e.g. the GXGXXG/A loop near the N-termini). In spite of this, they only have 45.6% of their residues in the same accessibility class (e.g. buried, half-bured, or exposed).

Type C similarity: Macromycin (2MCM) and an Immunoglobulin constant domain (2FBJ_L; below), on the other hand, have a much higher degree of residues in the same accessibility class (59.2%), despite no apparent functional or sequence similarity.

Secondary structure conservation

Type B similarity: the N- and C- terminal lobes of aspartyl proteinases are very likely to have diverged from a common ancestor. The N- terminal lobe of Renin (1RNE) and the C-terminal lob ov Pepsin (2PEP) are shown below. Not only are they similar structures, but they both contribute the same residue (i.e. an aspartic acid) to a common active site. Moreover, the existence of monomeric aspartyl proteinases in viruses (i.e. which dimerise rather than consist of a two domain protein) reinforces the relationship between N- and C- terminal lobes. Despite this relationship, only 42.8 % of the residues are of the same secondary structure type.

Type C similarity: Cytochrome b562 (256B_A) and Apolipoprotein (1LPE) are both four helix bundles, and despite a lack of sequence or functional similarity, these two protein show a higher degree of secondary structure identity (78.3 %) than the type B similarity shown above.