Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1.

Kurokawa S, Eriksson S, Rose KL, Wu S, Motley AK, Hill S, Winfrey VP, McDonald WH, Capecchi MR, Atkins JF, Arnér ES, Hill KE, Burk RF
Free Radic Biol Med. 2014 69: 67-76

PMID: 24434121 · PMCID: PMC3960317 · DOI:10.1016/j.freeradbiomed.2014.01.010

Mouse selenoprotein P (Sepp1) consists of an N-terminal domain (residues 1-239) that contains one selenocysteine (U) as residue 40 in a proposed redox-active motif (-UYLC-) and a C-terminal domain (residues 240-361) that contains nine selenocysteines. Sepp1 transports selenium from the liver to other tissues by receptor-mediated endocytosis. It also reduces oxidative stress in vivo by an unknown mechanism. A previously uncharacterized plasma form of Sepp1 is filtered in the glomerulus and taken up by renal proximal convoluted tubule (PCT) cells via megalin-mediated endocytosis. We purified Sepp1 forms from the urine of megalin(-/-) mice using a monoclonal antibody to the N-terminal domain. Mass spectrometry revealed that the purified urinary Sepp1 consisted of N-terminal fragments terminating at 11 sites between residues 183 and 208. They were therefore designated Sepp1(UF). Because the N-terminal domain of Sepp1 has a thioredoxin fold, Sepp1(UF) were compared with full-length Sepp1, Sepp1(Δ240-361), and Sepp1(U40S) as a substrate of thioredoxin reductase-1 (TrxR1). All forms of Sepp1 except Sepp1(U40S), which contains serine in place of the selenocysteine, were TrxR1 substrates, catalyzing NADPH oxidation when coupled with H2O2 or tert-butylhydroperoxide as the terminal electron acceptor. These results are compatible with proteolytic cleavage freeing Sepp1(UF) from full-length Sepp1, the form that has the role of selenium transport, allowing Sepp1(UF) to function by itself as a peroxidase. Ultimately, plasma Sepp1(UF) and small selenium-containing proteins are filtered by the glomerulus and taken up by PCT cells via megalin-mediated endocytosis, preventing loss of selenium in the urine and providing selenium for the synthesis of glutathione peroxidase-3.

Copyright © 2014 Elsevier Inc. All rights reserved.

MeSH Terms (13)

Animals Biological Transport Endocytosis Glutathione Peroxidase Hydrogen Peroxide Kidney Glomerulus Kidney Tubules, Proximal Mice Oxidation-Reduction Protein Structure, Tertiary Selenocysteine Selenoproteins Thioredoxin Reductase 1

Connections (2)

This publication is referenced by other Labnodes entities: