Abstract
Integrin αIIbβ3, a glycoprotein complex expressed at the platelet surface, is involved in platelet aggregation and contributes to primary haemostasis. Several integrin αIIbβ3 polymorphisms prevent the aggregation that causes haemorrhagic syndromes, such as Glanzmann thrombasthenia (GT). Access to 3D structure allows understanding the structural effects of polymorphisms related to GT. In a previous analysis using Molecular Dynamics (MD) simulations of αIIb Calf-1 domain structure, it was observed that GT associated with single amino acid variation affects distant loops, but not the mutated position. In this study, experiments are extended to Calf-1, Thigh, and Calf-2 domains. Two loops in Calf-2 are unstructured and therefore are modelled expertly using biophysical restraints. Surprisingly, MD revealed the presence of rigid zones in these loops. Detailed analysis with structural alphabet, the Proteins Blocks (PBs), allowed observing local changes in highly flexible regions. The variant P741R located at C-terminal of Calf-1 revealed that the Calf-2 presence did not affect the results obtained with isolated Calf-1 domain. Simulations for Calf-1 + Calf-2, and Thigh + Calf-1 variant systems are designed to comprehend the impact of five single amino acid variations in these domains. Distant conformational changes are observed, thus highlighting the potential role of allostery in the structural basis of GT.
Highlights
Integrins are a large protein family composed of heterodimeric receptors composed of α and β subunits [1]
Using new strategies in Molecular Dynamics (MD), in 2017, we studied the effect of seven variants of the αIIb Calf-1 domain, which are known to impair αIIbβ3 integrin expression in Glanzmann thrombasthenia (GT)
The second region is long enough to be beyond the scope of default loop-modelling algorithms [21], with no repetitive secondary structure [22,23] and high flexibility content [24,25,26]
Summary
Integrins are a large protein family composed of heterodimeric receptors composed of α and β subunits [1]. The human integrin αIIbβ is an essential complex implicated in fibrinogen-dependent platelet aggregation and thrombus formation, maintaining primary hemostasis [2]. Each subunit of the αIIbβ structure can be defined in 3 regions with the largest one, i.e., the extracellular ectodomain (959 and 693 residues in α and β subunits respectively), being a single spanning transmembrane region and a small C-terminus cytoplasmic region. It is hypothesized that the presence of fibrinogen stimulates the pathways resulting in the opening of the αIIbβ structure. The opening results in a separation of the two subunits, maintaining an interface at one position that is critical for the binding of fibrinogen [4] (see Figure 1 of [5] for more details). The association of the transmembrane helices with αIIb and β3 subunits plays a critical role in maintaining the inactive state [6]
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