The first epidermal growth factor-like domain of the low-density lipoprotein receptor contains a noncanonical calcium binding site

Biochemistry
S MalbyA K Downing

Abstract

Removal of cholesterol-containing particles from the circulation is mediated by the low-density lipoprotein (LDL) receptor. Upon ligand binding, the receptor-ligand complex is endocytosed, and the ligand is released. The important biological role of the LDL receptor (LDLR) has been highlighted by the identification of more than 400 LDLR mutations that are associated with familial hypercholesterolemia. The extracellular region of the LDLR is modular in nature and principally comprises multiple copies of ligand binding, epidermal growth factor-like (EGF), and YWTD-type domains. This report describes characterization of the calcium binding properties of the tandem pair of EGF domains. While only the C-terminal EGF module contains the consensus sequence associated with calcium binding, a noncanonical calcium binding site in the N-terminal domain has been revealed using solution NMR spectroscopy. The calcium dissociation constants for the N- and C-terminal sites have been measured under physiologically relevant pH and ionic strength conditions using a combination of solution NMR, intrinsic protein fluorescence, and chromophoric chelator methods to be approximately 50 microM and approximately 10-20 microM, respectively. Identificatio...Continue Reading

References

Feb 20, 1999·Journal of Molecular Biology·R S SmallridgeA K Downing
Feb 25, 2000·Journal of Molecular Biology·J M WernerA K Downing
Sep 1, 1994·Journal of Biomolecular NMR·B A Johnson, R A Blevins

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Citations

Dec 17, 2003·Current Opinion in Structural Biology·Gabby Rudenko, Johann Deisenhofer
Aug 31, 2006·Biochemistry·Kristina E M PerssonSuely M Rezende
Jan 22, 2010·The Journal of Biological Chemistry·Florentina PenaIneke Braakman
Jun 15, 2005·Annual Review of Biochemistry·Hyesung Jeon, Stephen C Blacklow
Dec 4, 2013·Journal of Lipid Research·My-Anh NguyenThomas A Lagace
Jun 10, 2005·FEBS Letters·Raimund WagenerMats Paulsson
Jun 26, 2012·Journal of Molecular Biology·Yingnan ZhangDaniel Kirchhofer
Mar 8, 2016·Traffic·Lars EllgaardIneke Braakman
Apr 28, 2017·EMBO Reports·Hidenori HiraiTerukazu Nogi
Oct 8, 2003·The Journal of Biological Chemistry·Julie PannequinGraham S Baldwin
Aug 14, 2013·Clinical Chemistry and Laboratory Medicine : CCLM·Indra Ramasamy
Oct 12, 2018·Science Translational Medicine·Eun Kyung SongTae Joo Park

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