Haptoglobin and the related haptoglobin protein: the -terminus makes the difference.

Haptoglobin related protein (Hpr) is a component of the trypanosome lytic factor (TLF), a complex acting in the innate immune response against African trypanosomes. Like haptoglobin (Hp), Hpr binds hemoglobin (Hb) in the blood, but unlike Hp, Hpr does not bind the CD163 receptor. Moreover, unlike Hp, Hpr retains the -terminal signal peptide that is required for the association with Apolipoprotein L-1 (ApoL-1), a component of the TLF complex. Here, the molecular model of human Hpr has been built based on the high sequence identity with human Hp (91%). The structural bases of Hpr:Hpr dimerization and Hpr recognition by Hb and Hp receptor (HpHbR) have been analyzed in parallel with those of Hp:Hp, Hp:Hb, and HpHbR:Hp:Hb complexes. We show that the Cys33-Cys33 intermolecular disulfide bridge that stabilizes the Hp1:Hp1 complex is replaced by the Phe33, Pro34, and Phe48 hydrophobic core in the Hpr:Hpr dimer. Moreover, we show that the -terminal peptide of Hpr participates in the stabilization of the Hpr:Hpr dimer. Thus, the -terminal peptide seems to have been retained in Hpr to mediate its critical role in the human innate immunity towards infection.Communicated by Ramaswamy H. Sarma.