Theta defensin

Structure

θ-defensins are cyclic peptides of 18 amino acids (~2 kDa), possessing antimicrobial activity against a range of Gram-positive and Gram-negative bacteria, fungi, and some retroviruses. They consist of a pair of antiparallel β-sheets linked by three disulfide bonds arranged as a ladder along the sheets to form an extremely stable structure. Additionally, the peptides may self-associate into trimers.

Biosynthesis

In rhesus macaque (Macaca mulatta) and olive baboon (Papio anubis), θ-defensins are produced from precursor proteins with 76 amino acids each. A single nine amino acid peptide is derived from each precursor. Two of these nine amino acid peptides are spliced together to form the circular 18 amino acid defensin. Since there are two precursor genes (rhesus theta defensin RTD-1 and RTD-2) they can form 3 different mature θ-defensins: the homodimer of processed RTD-1, The homodimer of processed RTD-2 or the heterodimer composed of both precursors. The heterodimeric form is the most abundant.

In the olive baboon, four θ-defensin precursor genes have been isolated: BTD-a, BTD-b, BTD-c and BTD-d, which encode subunits A, B, C and D. These four subunits could theoretically combine to produce 10 different processed defensins. However, only five have been observed: consisting of subunits A+A, A+B, A+C, A+D and B+B (Referred to as BTD-3, BTD-1, BTD-4, BTD7 and BTD-2 respectively). Finally, orangutan genomes encode 4 θ-defensin precursor genes and gibbon genomes encode 2.

Activity

Antimicrobial activity has been reported against bacteria, fungi, enveloped viruses, and protozoa. Antimicrobial activity is generally through binding to and disrupting the cell membrane. Antiviral activity appears to derive from their binding to the sugar component of glycoproteins and blocking the entry of viruses into the cell.

Evolution

Genesis

θ-defensins are extremely divergent members of the defensin protein superfamily which includes alpha-, beta- and big-defensins. The θ-defensins appear to have evolved from α-defensin genes around 40 million years ago in Old World monkeys. Compared to their α-defensin ancestors, θ-defensin genes are truncated into two halves.

Inactivaton

Although great apes do not produce θ-defensin proteins, their genomes do encode θ-defensin genes which are transcribed to mRNA but not translated due to a premature stop codon. When the mature defensin that would be expressed is chemically synthesised in a laboratory, it shows antimicrobial activity (including anti-retrovirus, leading to the name "retrocyclin"). It is unknown whether this pseudogenisation gave a selective advantage or was due to genetic drift. The anti-HIV activity of retrocyclins has been further enhanced by protein engineering efforts with the aim of generating a viable treatment.

References

References

1. (26 September 2014). "The chemistry and biology of theta defensins.". Angewandte Chemie International Edition in English.
2. (October 2004). "Retrocyclins: using past as prologue". Curr. Protein Pept. Sci..
3. (Jun 2014). "Evolution of primate α and θ defensins revealed by analysis of genomes". Molecular Biology Reports.
4. (October 1999). "A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins". Science.
5. (September 2001). "Circular minidefensins and posttranslational generation of molecular diversity". J. Leukoc. Biol..
6. (February 2002). "Homodimeric θ-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides". J. Biol. Chem..
7. (December 2008). "Isolation, synthesis, and antimicrobial activities of naturally occurring θ-defensin isoforms from baboon leukocytes". Infect. Immun..
8. (Sep 4, 2007). "Retrocyclin-2: structural analysis of a potent anti-HIV theta-defensin". Biochemistry.
9. (Nov 21, 2010). "Naturally occurring circular proteins: distribution, biosynthesis and evolution.". Organic & Biomolecular Chemistry.
10. (Apr 28, 2009). "Reawakening retrocyclins: ancestral human defensins active against HIV-1.". PLOS Biology.
11. (Feb 19, 2002). "Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1.". Proceedings of the National Academy of Sciences of the United States of America.