5bjt
From Proteopedia
Revision as of 06:50, 5 April 2017
Crystal structure of human FcRn with a peptide inhibitor at multiple sites
Structural highlights
Disease[B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Function[FCGRN_HUMAN] Binds to the Fc region of monomeric immunoglobulins gamma. Mediates the uptake of IgG from milk. Possible role in transfer of immunoglobulin G from mother to fetus. [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Publication Abstract from PubMedThe neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity. Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.,Pyzik M, Rath T, Kuo TT, Win S, Baker K, Hubbard JJ, Grenha R, Gandhi A, Kramer TD, Mezo AR, Taylor ZS, McDonnell K, Nienaber V, Andersen JT, Mizoguchi A, Blumberg L, Purohit S, Jones SD, Christianson G, Lencer WI, Sandlie I, Kaplowitz N, Roopenian DC, Blumberg RS Proc Natl Acad Sci U S A. 2017 Mar 22. pii: 201618291. doi:, 10.1073/pnas.1618291114. PMID:28330995[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Badger, J | Nienaber, V | Amyloid | Amyloidosis | Cell membrane | Disease mutation | Disulfide bond | Glycation | Glycoprotein | Igg-binding protein | Immune response | Immune system-inhibitor complex | Immunoglobulin binding protein | Immunoglobulin domain | Mhc i | Pyrrolidone carboxylic acid | Receptor | Secreted | Transmembrane
