This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marinò, M. Articles by McCluskey, R. T. Search for Related Content PubMed PubMed Citation Articles by Marinò, M. Articles by McCluskey, R. T. Pubmed/NCBI databases Substance via MeSH Hazardous Substances DB THYROGLOBULIN

Binding of the Low Density Lipoprotein Receptor-Associated Protein (RAP) to Thyroglobulin (Tg): Putative Role of RAP in the Tg Secretory Pathway

Department of Endocrinology (M.M., L.C., S.L., A.P.), University of Pisa, 56124 Pisa, Italy; and Pathology Research Laboratory (M.M., R.T.M.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Address all correspondence and requests for reprints to: Michele Marinò, Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: m.marino{at}endoc.med.unipi.it

The 39–44 kDa protein known as the receptor-associated protein binds to members of the low density lipoprotein receptor family and is found within cells that express these receptors. The receptor-associated protein has been shown to prevent premature binding of ligands to the receptors in the endoplasmic reticulum and to promote proper folding and transport of the receptors in the secretory pathway. In the thyroid, megalin (a low-density lipoprotein receptor family member) serves as an endocytic receptor for thyroglobulin. Here we present evidence that the receptor-associated protein can bind to thyroglobulin, which suggests a novel function of the receptor-associated protein, namely binding of certain megalin ligands possibly during the biosynthetic pathway.

In solid-phase assays thyroglobulin was shown to bind to the receptor-associated protein with moderately high affinity (mean between K_d and K_i = 39.8 nM), in a calcium-dependent and saturable manner. The receptor-associated protein also bound to a native carboxyl-terminal 230-kDa thyroglobulin polypeptide, which markedly reduced binding of intact thyroglobulin to the receptorassociated protein, indicating that the receptor-associated protein binding sites of thyroglobulin are located in the carboxyl-terminal portion of the molecule. In addition to thyroglobulin, the receptor-associated protein specifically bound to another megalin ligand, namely lipoprotein lipase. Because lipoprotein lipase markedly reduced receptor-associated protein binding to thyroglobulin, we concluded that the receptor-associated protein uses the same binding site/s to bind to thyroglobulin and lipoprotein lipase. Evidence of thyroglobulin binding to the receptor-associated protein was also obtained in vivo and in cultured thyroid cells. Thus, anti-receptor-associated protein antibodies precipitated intact thyroglobulin from extracts prepared from rat thyroids and cultured thyroid cells (FRTL-5 cells). Chase experiments after inhibition of protein synthesis in FRTL-5 cells showed that thyroglobulin interacts with the receptor-associated protein shortly after the beginning of thyroglobulin biosynthesis.

This article has been cited by other articles:

				S. Lisi, R. Botta, A. Pinchera, A. B. Collins, S. Refetoff, P. Arvan, G. Bu, L. Grasso, V. Marshansky, S. Bechoua, et al. Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1160 - C1167. [Abstract] [Full Text] [PDF]

				W. Pan, A. J. Kastin, T. C. Zankel, P. van Kerkhof, T. Terasaki, and G. Bu Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier J. Cell Sci., October 1, 2004; 117(21): 5071 - 5078. [Abstract] [Full Text] [PDF]

				E. Sargsyan, M. Baryshev, L. Szekely, A. Sharipo, and S. Mkrtchian Identification of ERp29, an Endoplasmic Reticulum Lumenal Protein, as a New Member of the Thyroglobulin Folding Complex J. Biol. Chem., May 3, 2002; 277(19): 17009 - 17015. [Abstract] [Full Text] [PDF]