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Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis
and anti-FcRn albumin-blocking antibodies
#MMPMID24764301
Sand KM
; Dalhus B
; Christianson GJ
; Bern M
; Foss S
; Cameron J
; Sleep D
; Bjørås M
; Roopenian DC
; Sandlie I
; Andersen JT
J Biol Chem
2014[Jun]; 289
(24
): 17228-39
PMID24764301
show ga
Albumin is the most abundant protein in blood and plays a pivotal role as a
multitransporter of a wide range of molecules such as fatty acids, metabolites,
hormones, and toxins. In addition, it binds a variety of drugs. Its role as
distributor is supported by its extraordinary serum half-life of 3 weeks. This is
related to its size and binding to the cellular receptor FcRn, which rescues
albumin from intracellular degradation. Furthermore, the long half-life has
fostered a great and increasing interest in utilization of albumin as a carrier
of protein therapeutics and chemical drugs. However, to fully understand how FcRn
acts as a regulator of albumin homeostasis and to take advantage of the
FcRn-albumin interaction in drug design, the interaction interface needs to be
dissected. Here, we used a panel of monoclonal antibodies directed towards human
FcRn in combination with site-directed mutagenesis and structural modeling to
unmask the binding sites for albumin blocking antibodies and albumin on the
receptor, which revealed that the interaction is not only strictly pH-dependent,
but predominantly hydrophobic in nature. Specifically, we provide mechanistic
evidence for a crucial role of a cluster of conserved tryptophan residues that
expose a pH-sensitive loop of FcRn, and identify structural differences in
proximity to these hot spot residues that explain divergent cross-species binding
properties of FcRn. Our findings expand our knowledge of how FcRn is controlling
albumin homeostasis at a molecular level, which will guide design and engineering
of novel albumin variants with altered transport properties.
|Albumins/*metabolism
[MESH]
|Amino Acid Sequence
[MESH]
|Antibodies, Blocking/immunology
[MESH]
|Antibodies, Monoclonal/immunology
[MESH]
|Binding Sites
[MESH]
|Histocompatibility Antigens Class I/*chemistry/genetics/immunology/metabolism
[MESH]
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