Functional Role of a Conserved Sequence Motif in the Oxygen-dependent Degradation Domain of Hypoxia-inducible Factor 1 alpha in the Recognition of p53

Hypoxia-inducible factor 1 alpha (HIF1 alpha) is a transcription factor that plays a key role in the adaptation of cells to low oxygen stress and oxygen homeostasis. The oxygen-dependent degradation (ODD) domain of HIF1 alpha is responsible for the negative regulation of HIF1 alpha in normoxia. The interactions of the HIF1 alpha ODD domain with partner proteins such as von Hippel-Lindau tumor suppressor (pVHL) and p53 are mediated by two sequence motifs, the N- and C-terminal ODD (NODD and CODD). Multiple sequence alignment with HIF1 alpha homologs from human, monkey, pig, rat, mouse, chicken, frog, and zebrafish has demonstrated that the NODD and CODD motifs have noticeably high conservation of the primary sequence across different species and isoforms. In this study, we carried out molecular dynamics simulation of the structure of the HIF1 alpha CODD motif in complex with the p53 DNA-binding domain (DBD). The structure reveals specific functional roles of highly conserved residues in the CODD sequence motif of HIF1 alpha for the recognition of p53.

Comparative Genomics Study of Interferon-alpha Receptor-1 in Humans and Chimpanzees

The immune response-related genes have been suggested to be the most favorable genes for positive selection during evolution. Comparing the entire DNA sequence of chimpanzee chromosome 22 (PTR22) with human chromosome 21 (HSA21), we have identified 15 orthologs having indel in their coding sequences. Among them, interferon-alpha receptor-1 gene (IFNAR1), an immuneresponse- related gene, is subjected to comparative genomic analysis. Chimpanzee IFNAR1 showed the same genomic structure as human IFNAR1 (11 exons and 10 introns) except the 3 bp insertion in exon 4. The sequence alignment of IFNAR1 coding sequence indicated that "ISPP" amino acid sequence motif is highly conserved in chimpanzee and other animals including mouse and chicken. However, the human IFNAR1 shows that one proline residue is missing in the sequence motif. The homology modeling of the IFNAR1 structures suggests that the proline deletion in human IFNAR1 leads to the formation of the following alpha-helix, whereas two sequential prolines in chimpanzee IFNAR1 inhibit it. As a result, human IFNAR1 may adopt a characteristic structure distinct from chimpanzee IFNAR1. This human specific trait could contribute to specific immune response in the most optimized manner for humans. Further molecular biological studies on the IFNAR1 will help us to gain insights into the molecular implication of species specific host-pathogen interaction in primate evolution.