PDBsum entry: 1xfe

Lipid transport, endocytosis/exocytosis

PDB id: 1xfe

Contents

Protein chain

83 a.a. *

Metals

_CA ×2

* Residue conservation analysis

PDB id:

1xfe

Name:

Lipid transport, endocytosis/exocytosis

Title:

Solution structure of the la7-egfa pair from the ldl receptor

Structure:

Low-density lipoprotein receptor. Chain: a. Fragment: sequence database residues 272-353: includes ldl- receptor class a 7 (residues 274-313), egf-like 1 (314- 353). Synonym: ldl receptor, la7-egfa pair. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ldlr. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Other_details: gateway expression system (invitrogen)

NMR struc:

15 models

Authors:

N.Beglova,H.Jeon,C.Fisher,S.C.Blacklow

Key ref:

N.Beglova et al. (2004). Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor. Mol Cell, 16, 281-292. PubMed id: 15494314 DOI: 10.1016/j.molcel.2004.09.038

Date:

14-Sep-04 Release date: 02-Nov-04

Protein chain

P01130  (LDLR_HUMAN) -  Low-density lipoprotein receptor

Seq: 860 a.a.

Struc: 83 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.molcel.2004.09.038

Mol Cell 16:281-292 (2004)

PubMed id: 15494314

Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor.

N.Beglova, H.Jeon, C.Fisher, S.C.Blacklow.

ABSTRACT

Low-density lipoprotein (LDL) receptors bind lipoprotein particles at the cell surface and release them in the low pH environment of the endosome. The published structure of the receptor determined at endosomal pH reveals an interdomain interface between its beta propeller and its fourth and fifth ligand binding (LA) repeats, suggesting that the receptor adopts a closed conformation at low pH to release LDL. Here, we combine lipoprotein binding and release assays with NMR spectroscopy to examine structural features of the receptor promoting release of LDL at low pH. These studies lead to a model in which the receptor uses a pH-invariant scaffold as an anchor to restrict conformational search space, combining it with flexible linkers between ligand binding repeats to interconvert between open and closed conformations. This finely tuned balance between interdomain rigidity and flexibility is likely to represent a shared structural feature in proteins of the LDL receptor family.

Selected figure(s)

Figure 5.
Figure 5. Structure and dynamics of the LA7-EGF_A domain pair at neutral pH(A) Plot of hNOE as a function of residue number for the LA7-EGF_A pair. The hNOE profile of the LA7-EGF_A pair is the same at pH 5.2, 6.5, and 7.0, indicating the existence of an interface that does not vary with pH.(B) Best fit superposition of the 15 lowest energy neutral pH NMR structures of the LA7-EGF_A domain pair. The Cα trace and bound calcium ions are shown.(C) Ribbon trace of the LA7-EGF_A structure. The LA7 ribbon is blue, and the EGF_A ribbon is red. Disulfide bonds and calcium-coordinating side chains are illustrated in CPK colors. Bound calcium ions are yellow.(D) Close-up stereo view of the interface seen in the neutral pH NMR structure. Residues in a hydrophobic cluster that comprises the interface are labeled. Labels of residues harboring FH mutations are boxed.(E) Best fit superposition (stereo) of the neutral pH NMR structure (blue) onto the corresponding region of the crystal structure determined at endosomal pH (yellow).

Figure 7.
Figure 7. Schematic Proposing How Fixed and Flexible Connections among Domains Cooperate to Permit Interconversion between Open and Closed Conformations in Response to pHLA7, EGF_A, and EGF_B constitute a rigid scaffold that is invariant with pH. Wavy lines identify modules linked by connections likely to be flexible at the indicated pH, with freedom of movement for the ligand binding modules at neutral pH increasing as a function of distance from the rigid scaffold. LA modules are green, EGF-like modules are yellow, and the β propeller domain is pink.

The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 16, 281-292) copyright 2004.

Figures were selected by an automated process.