Covalent structure of human haptoglobin: a serine protease homolog.

Abstract

The complete amino acid sequences and the disulfide arrangements of the two chains of human haptoglobin 1-1 were established. The al and P chains of haptoglobin contain 83 and 245 residues, respectively. Comparison of the primary structure of haptoglobin with that of the chymotrypsinogen family of serine proteases revealed a significant degree of chemical similarity. ITe probability was less than 10-5 that the chemical similarity of the P chain of haptoglobin to the proteases was due to chance. The amino acid sequence of the P chain of haptoglobin is 29-33% identical to bovine trypsin, bovine chymotrypsin, porcine elastase, human thrombin, or human plasmin. Comparison of haptoglobin al chain to activation peptide regions of the zymogens revealed an identity of 25% to the fifth "kringle" region of the activation peptide of plasminogen. The probability was less than 0.014 that this similarity was due to chance. These results strongly indicate haptoglo in to be a homolog of the chymotrypsinogen family of serine proteases. Alignment of the ,Bchain sequence of haptoglobin to the serine proteases is remarkably consistent except for an insertion of 16 residues in the region corresponding to the methionyl loop of the serine proteases. The active-site residues typical of the serine proteases,-histidine-57 and serine-195, are replaced in haptoglobin by lysine and alanine, respectively; however, aspartic acid-102 and the trypsin specificity residue, aspartic acid-189, do occur in haptoglobin. Haptoglobin and the serine proteases represent a striking example of homologous proteins with different biological functions.

Structural similarities among concanavalin A, haptoglobin, and trypsin

“…In the cases of polar and weak amino acids, differences between Con A and trypsin are lower than between Hpfl and trypsin, in spite of the latter well-known homology [3].…”

“…Hp of genetic type l-l is a tetramer, composed of two a (light) chains and twop (heavy) chains, linked by disulphide bridges [2]. Amino acid sequence analysis of the Hp ,@ chain pointed to its chemical similarity to the chymotrypsinogen family of serine proteases [3]. This homology was also confirmed in the three-dimensional structures of trypsin and HP 14951.…”

“…Alignment of amino acid sequences of Con A (237 amino acids) to Hpfi (245 amino acids) and to trypsin (223 amino acids) shows significant chemi- chain and trypsin were taken from [3], and Con A from [7].…”

“…During identification of,&turns in regions of polypeptide chain reversals in Hp, some analogies with Con A emerged [ 11. The positions corresponding to the proteolytic active site residues of trypsin, His-57 and Ser-195 (replaced in Hp.& by Lys and Ala, respectively) [3], exist in Con A as His-51 and Ser-189. The trypsin-specific residue Asp-189 as well as Asp-102 and Asp-194 (forming an internal ion pair with the a-amino terminal resi-due in serine proteases), present also in Hp, have their equivalents in Con A as Glu-183, Glu-102 and Glu-192, respectively.…”

Extracellular Chaperones

“…Humans express one of three different haptoglobin phenotypes (Hp 1-1, Hp 1-2 or Hp 2-2) depending on the presence of two principal alleles (Hp1 and Hp2) coding for the α and β chains which associate covalently via disulphide linkage. The α 1 , α 2 and β chain peptides are 9.2 kDa, 15.9 kDa and 27.2 kDa, respectively [68]. Similar to clusterin, haptoglobin is heavily glycosylated.…”