Structural characterization of mouse serum albumin recycling mechanism

Human serum albumin (hSA) is the most important multifunctional transporter in the blood, carrying various substances like fatty acids, thyroxine, heme, bilirubin, metals, nitric oxide and thiol-containing molecules. Albumin primary feature is the 19 to 21 days serum half-life in humans and has been studied as a putative carrier to improve drug pharmacokinetics and pharmcodynamics. Albumin’s long half-life depends on its pH-dependent recycling by the neonatal Fc receptor (hFcRn). In the past decade, hSA and hFcRn were widely studied structurally as monomers and in complexes, elucidating the molecular mechanism behind their fine interplay. However, preclinical trials rely on mouse model to study the safety and applicability of novel drugs before human testing. Recent studies highlighted intrinsic differences in binding of hSA to hFcRn and the mouse neonatal Fc receptor (mFcRn), as well as between mouse serum albumin (mSA) and hFcRn/mFcRn. Specific mouse strains were also engineered not to express endogenous albumin or, on the other hand, to express both human albumin and receptors, underlining the need for a good model to study albumin-based drugs. On the other hand, nor mouse serum albumin neither its receptor have been structurally characterized yet. Studying this interaction is critical in the context of development of albumin-based therapeutics. Recent studies obtained indirect evidence that, while hSA has been shown to use both its domain I and III for interacting with hFcRn, mSA mainly relies on its domain III. A mSA-mFcRn model could be used to precisely design drugs, retaining the required pharmacokinetic properties in humans and accelerating the process of pre-clincal testing and approval. In order to fill the knowledge gap between humans and mice, this work aims to obtain the first high resolution structure model of mouse serum albumin.