What are they, and do they share a common ancestor? How far back in evolutionary time must we go to find them?

If none are known, what computational tools might be used to search for such examples?

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    $\begingroup$ Your current question ("Are there any examples of proteins with no or minimal sequence identity, but high structural homology?") uses the term "homology" in a wrong way: Homology refers to common ancestry. So "homology" is binary (like being pregnant), and there is no such thing as "structural homology" (or "high homology" etc.). A more exact question would be: "Are there proteins with little sequence similarity but a very similar structure (and do they share a common ancestor)?" $\endgroup$ Jun 6, 2012 at 11:57
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    $\begingroup$ My god, you're right. Apologies for the oversight, and question edited accordingly. Thanks! $\endgroup$ Jun 6, 2012 at 20:04

4 Answers 4


The answer is that common folds are discovered in sequences which are completely divergent where essentially no alignment can be found by conventional means.

David Eisenberg's group created profiles based on alignments from known structures which were more sensitive to discovering whether a given protein sequence was related to a given structure, solving what he called the 'inverse folding problem'. More recently HMMs have been used from raw aligned sequences which are even more sensitive to predicting whether a given protein structural family can be found in a query sequence. PsiBlast also deserves a mention as a method that builds such a profile on the fly. It can come back with sequences that are so divergent that they are probably not really related (personal experience).

A classic example of this is hexokinase, an enzyme that phosphorylates sugars - which shows up in single cell eukaryotes and all animals. When the structure of actin was solved, it proved to have the same core fold as hexokinase. Actin is one of the most venerable proteins known in eurkaryotes, so this is now called the actin fold. None of the software mentioned above would detect this relationship. (I just verified this with psiblast).

Its probably not true all the time, but it probably happens a lot that sequences with the same protein fold are so different that they cannot be detected by any of these means. Most genomes that are sequenced have dozens or hundreds of 'novel genes' - 40% of E coli is still uncharacterized. Either there are novel folds popping up spontaneously over short evolutionary time frames or the possible sequences for many protein folds is quite large. My expectation is that a novel protein sequence can emerge with the same fold in quite quickly, especially in bacteria.

  • $\begingroup$ These are all helpful answers, but I think this one is most complete. Thanks! $\endgroup$ Jun 10, 2012 at 1:36

This paper published last year, address the answer for your question, about computational methods, they mention 3 principal algorithms for structural alignment of proteins:

  • Structural alignment directly at the level of C atoms.
  • The second class of algorithms first uses the SSEs (Secondary Structure Elements) to carry out an approximate alignment, and then uses the C atoms.
  • The final class of algorithms uses geometric hashing.

And finally you could find useful this paper for an example of this kind of analysis with structural analyses of metabolic families.



The group of Andrei Lupas studies this. He argues that the vast majority of folds arose only once, so that proteins that share a fold are homologous, even if their sequences have diverged. See for example this paper: "Evolutionary Relationships of Microbial Aromatic Prenyltransferases" where they show that there are subtle sequence similarities between two protein families of the same fold, arguing for a common ancestor.


An example possibly worth taking a look at is the variable surface glycoprotein of the bloodstream form of Trypanosoma brucei.

Trypanosomes are the causative agent of sleeping sickness, and the entire cell surface is covered by a single glycoprotein called the variable surface glycoprotein, or VSG. (see here for more information)

These parasitic protozoans have the ability to 'fool' the immune response by antigenic variation. At any one time just a single VSG is expressed on the surface, but (very rarely) a trypanosome may express a different VSG gene product. Thus if the immune response succeeds in eliminating all trypanosomes expressing VSG-A, but there exists in the population just one parasite which has switched coat, this variant will poliferate as it effectively presents a different antigen to the host's defenses (and a second immune response will result).

There is litte sequence identity between different VSGs but they are homologous (descended from a common ancestor).

The crystal structure of the N-terminal domain of two different VSGs (MITat1.2 and ILTat1.24) have been solved (Blum et al. 1993; Freymann et al., 1993). Despite the low sequence identity (~16%), the structures are almost identical.

One other very interesting property of all VSGs is that they are covalently anchored to the plasma membrane via a (C-terminus) glycosylphosphatidylinositol anchor (or GPI anchor).


  • Blum, M. L., Down, J. A., Gurnett, A. M., Carrington, M., Turner, M. J., and Wiley, D. C. (1993) Nature 362, 603-609 [pubmed]

  • Freymann, D., Down, J., Carrington, M., Roditi, I., Turner, M., and Wiley, D. (1990) 2.9 A resolution structure of the N-terminal domain of a variant surface glycoprotein from Trypanosoma brucei. J. Mol. Biol. 216, 141-160 [Pubmed]

The following reference contains much useful background information, and is free to all.

  • Chattopadhyay, A, Jones, N.G, Nietlispach,D, Nielsen, P.R., Voorheis, H.P., Mott H.R., Carrington, M. (2005) Structure of the C-terminal domain from Trypanosoma brucei variant surface glycoprotein MITat1.2. J. Biol. Chem., 280, 7228-7235 [Pubmed] [pdf]

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