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Conservation in decay accelerating factor (DAF) structure among primates
L Kuttner-Kondo1, V B Subramanian, J P Atkinson
1Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA.
Insights
The decay accelerating factor (DAF, CD55) is highly conserved across primates, with key functional sites remaining unchanged. Studies revealed variations in DAF protein isoforms and a Rhesus macaque model for a human blood group deficiency.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The decay accelerating factor (DAF, CD55) is crucial for preventing self-cell complement activation by inhibiting C3 convertases.
- DAF's functional sites are located within its four complement control protein (CCP) repeats, supported by a serine/threonine-rich region.
- Previous research proposed specific amino acid residues in DAF's CCPs as critical for C3 convertase interaction.
Purpose of the Study:
- To characterize the amino acid sequence and functional conservation of DAF in five non-human primate species.
- To investigate potential variations in DAF protein isoforms due to alternative splicing in the S/T-rich region.
- To identify primate models for human complement-related blood group phenotypes.
Main Methods:
- Amino acid sequence analysis of DAF in gorillas, chimpanzees, hamadryas baboons, Rhesus macaques, and patas monkeys.
- Comparative analysis of DAF homology with human sequences, focusing on putative ligand-interactive residues.
- Investigation of alternative splicing in the S/T-rich region and its impact on DAF protein expression.
Main Results:
- High amino acid homology to human DAF was observed (approx. 98% in great apes, 83% in Old World monkeys).
- Putative ligand-interactive residues within DAF's CCPs were fully conserved across all studied primates.
- Alternative splicing of the S/T region led to multiple DAF isoforms in chimpanzees but a single band in patas monkeys.
- A Rhesus macaque exhibited a 44-base pair deletion in CCP3, mimicking the human Cromer Dr(a-) blood group phenotype.
Conclusions:
- DAF's critical functional regions are evolutionarily conserved across diverse primate species.
- Variations in DAF alternative splicing contribute to protein isoform diversity.
- Non-human primates, particularly Rhesus macaques, offer valuable models for studying human complement disorders and blood group variations.
Abstract:
The decay accelerating factor (DAF, CD55) protects self cells from activation of autologous complement on their surfaces. It functions to disable the C3 convertases, the central amplification enzymes of the cascade. Its active site(s) are contained within four approximately 60 amino acid long units, termed complement control protein repeats (CCPs), which are suspended above the cell surface on a 68 amino acid long serine/threonine (S/T)-rich cushion that derives from three exons. We previously proposed a molecular model of human DAF's four CCPs in which certain amino acids were postulated to be recognition sites for the interaction between DAF and the C3 convertases. In the current study, we characterized DAF in five non-human primates: the great apes, gorilla and common chimpanzee, and the Old World monkeys: hamadryas baboon, Rhesus macaque, and patas monkey. Amino acid homology to human DAF was approximately 98% for the two great apes and 83% for the three Old World monkeys. The above cited putative ligand interactive residues were found to be fully conserved in all of the non-human primates, although there were amino acid changes outside of these areas. In the chimpanzee, alternative splicing of the S/T region was found potentially to be the source of multiple protein isoforms in erythrocytes, whereas in the patas monkey, similar alternative splicing was observed but only one protein band was seen. Interestingly, a Rhesus macaque was found to exhibit a phenomenon paralleling the human Cromer Dr(a-) blood group, in which a 44-base pair deletion in CCP3 leads to a frameshift and early STOP codon.