1HZ8

SOLUTION STRUCTURE AND BACKBONE DYNAMICS OF A CONCATEMER OF EGF-HOMOLOGY MODULES OF THE HUMAN LOW DENSITY LIPOPROTEIN RECEPTOR

Summary for 1HZ8

• Entry DOI: 10.2210/pdb1hz8/pdb
• Related: 1F5Y 1I0U 1LRX
• Descriptor: LOW DENSITY LIPOPROTEIN RECEPTOR, CALCIUM ION (2 entities in total)
• Functional Keywords: anti-parallel beta strands, calcium binding sites, lipid binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01130
• Total number of polymer chains: 1
• Total formula weight: 9081.17

Authors

Kurniawan, N.D.,Aliabadizadeh, K.,Brereton, I.M.,Kroon, P.A.,Smith, R. (deposition date: 2001-01-23, release date: 2001-08-15, Last modification date: 2024-11-13)

Primary citation

Kurniawan, N.D.,Aliabadizadeh, K.,Brereton, I.M.,Kroon, P.A.,Smith, R.
NMR structure and backbone dynamics of a concatemer of epidermal growth factor homology modules of the human low-density lipoprotein receptor.
J.Mol.Biol., 311:341-356, 2001

PubMed Abstract: The ligand-binding region of the low-density lipoprotein (LDL) receptor is formed by seven N-terminal, imperfect, cysteine-rich (LB) modules. This segment is followed by an epidermal growth factor precursor homology domain with two N-terminal, tandem, EGF-like modules that are thought to participate in LDL binding and recycling of the endocytosed receptor to the cell surface. EGF-A and the concatemer, EGF-AB, of these modules were expressed in Escherichia coli. Correct protein folding of EGF-A and the concatemer EGF-AB was achieved in the presence or absence of calcium ions, in contrast to the LB modules, which require them for correct folding. Homonuclear and heteronuclear 1H-15N NMR spectroscopy at 17.6 T was used to determine the three-dimensional structure of the concatemer. Both modules are formed by two pairs of short, anti-parallel beta-strands. In the concatemer, these modules have a fixed relative orientation, stabilized by calcium ion-binding and hydrophobic interactions at the interface. 15N longitudinal and transverse relaxation rates, and [1H]-15N heteronuclear NOEs were used to derive a model-free description of the backbone dynamics of the molecule. The concatemer appears relatively rigid, particularly near the calcium ion-binding site at the module interface, with an average generalized order parameter of 0.85+/-0.11. Some mutations causing familial hypercholesterolemia may now be rationalized. Mutations of D41, D43 and E44 in the EGF-B calcium ion-binding region may affect the stability of the linker and thus the orientation of the tandem modules. The diminutive core also provides little structural stabilization, necessitating the presence of disulfide bonds. The structure and dynamics of EGF-AB contrast with the N-terminal LB modules, which require calcium ions both for folding to form the correct disulfide connectivities and for maintenance of the folded structure, and are connected by highly mobile linking peptides.

PubMed: 11478865
DOI: 10.1006/jmbi.2001.4867

Experimental method

SOLUTION NMR