Haptoglobin

Haptoglobin has two key domains, a serine protease (SP) domain and a complement control protein (CPP) domain. Despite having this SP domain, haptoglobin is not an active protease as it has an incomplete catalytic triad. Instead, these SP domains are responsible for binding haemoglobin to form the complex. The CCP domain on the other hand is needed for binding two molecules of haptoglobin together.

CPP Domain

CCP domains typically have β strands arranged as two sheets packed together, known as a β sandwich, and four conserved cysteine residues which form two disulphide bridges. However, the haptoglobin CCP domain lacks Cys₆₈ and instead Cys₃₃ forms an interchain disulphide bridge that links two CCP domains together. Furthermore, the two haptoglobin CCP domains use a β-strand swap in order to dimerise, a process not seen before by CCP domains. 

Interaction

There is a specific interaction between the CCP and SP domains which causes the haptoglobin to have a rigid structure.

SP Domain

Haptoglobin has a characteristic SP domain; two anti-parallel β-barrels, each made up of 6 β-strands, with a few α-helices. There are also several surface loops, however these differ from typical SP domains in their length and conformation. The most significant difference is the extended loop 3, as this contains conserved residues and is known to bind CD163 as well as α-haemoglobin.  Small-angle X-ray scattering measurements confirmed this loop binds two CD163 receptors.