Sickle-cell haemoglobin polymerization: is it the primary pathogenic event of sickle-cell anaemia?

Abstract

Sickle cell anaemia is associated with a mutant haemoglobin, HbS, which forms polymers in the red blood cells of patients. The primary role of the HbS polymerization for the pathophysiology has been questioned: observations in patients and model organisms contradict deterministic scenarios of sickling crises triggered by polymerization. However, results with knock-out sickle-cell mice, which were cured by delaying HbS polymerization, reconfirm polymerization's primary role. To reconcile the contradictory observations, this article reviews recent findings on two steps in polymerization: homogeneous nucleation of fibres, and their growth. The fibre growth is faster by far than for any other protein ordered structure. This is due to a negligible free-energy barrier for incorporation into a fibre, determined by an entropy gain, stemming from the release of water molecules structured around HbS. The kinetics of fibre nucleation have shown that the formation of the polymer nucleus is preceded by a metastable droplet of a dense liquid. The properties of the dense liquid are sensitive functions of solution composition, including components in micro- and nanomolar amounts. This mechanism allows low-concentration solution components to strongly affect the nucleation kinetics, accounting for the high variability of the disease. These insights can potentially be utilized for control of HbS polymerization and treatment of the disease.