title: A unique tetrameric structure of deer plasma haptoglobin--an evolutionary advantage in the Hp 2-2 phenotype with homogeneous structure.
abstract: Similar to blood types, human plasma haptoglobin (Hp) is classified into three phenotypes: Hp 1-1, 2-1 and 2-2. They are genetically inherited from two alleles Hp 1 and Hp 2 (represented in bold), but only the Hp 1-1 phenotype is found in almost all animal species. The Hp 2-2 protein consists of complicated large polymers cross-linked by alpha2-beta subunits or (alpha2-beta)n (where n>or=3, up to 12 or more), and is associated with the risk of the development of diabetic, cardiovascular and inflammatory diseases. In the present study, we found that deer plasma Hp mimics human Hp 2, containing a tandem repeat over the alpha-chain based on our cloned cDNA sequence. Interestingly, the isolated deer Hp is homogeneous and tetrameric, i.e. (alpha-beta)4, although the locations of -SH groups (responsible for the formation of polymers) are exactly identical to that of human. Denaturation of deer Hp using 6 m urea under reducing conditions (143 mmbeta-mercaptoethanol), followed by renaturation, sustained the formation of (alpha-beta)4, suggesting that the Hp tetramers are not randomly assembled. Interestingly, an alpha-chain monoclonal antibody (W1), known to recognize both human and deer alpha-chains, only binds to intact human Hp polymers, but not to deer Hp tetramers. This implies that the epitope of the deer alpha-chain is no longer exposed on the surface when Hp tetramers are formed. We propose that steric hindrance plays a major role in determining the polymeric formation in human and deer polymers. Phylogenetic and immunochemical analyses revealed that the Hp 2 allele of deer might have arisen at least 25 million years ago. A mechanism involved in forming Hp tetramers is proposed and discussed, and the possibility is raised that the evolved tetrameric structure of deer Hp might confer a physiological advantage.
authors.affiliation: Institute of Biochemical Engineering, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: I H
authors.initials: IH
authors.lastname: Lai
authors.forename: Kung-Yu
authors.initials: KY
authors.lastname: Lin
authors.forename: Mikael
authors.initials: M
authors.lastname: Larsson
authors.forename: Ming Chi
authors.initials: MC
authors.lastname: Yang
authors.forename: Chuen-Huei
authors.initials: CH
authors.lastname: Shiau
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Liao
authors.forename: Simon J T
authors.initials: SJ
authors.lastname: Mao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003670:Deer / Q000097:blood*; D019143:Evolution, Molecular; D006242:Haptoglobins / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010802:Phylogeny; D011487:Protein Conformation; D011489:Protein Denaturation; D016415:Sequence Alignment
chemical_list: D000911:Antibodies, Monoclonal; C485359:HP protein, human; D006242:Haptoglobins; D006454:Hemoglobins