3SO6

Crystal structure of the LDL receptor tail in complex with autosomal recessive hypercholesterolemia PTB domain

3SO6 の概要

• エントリーDOI: 10.2210/pdb3so6/pdb
• 分子名称: LDL receptor adaptor protein, Low-density lipoprotein receptor (3 entities in total)
• 機能のキーワード: ptb, endocytic adaptor, receptor, ldl, ldlr, autosomal recessive hypercholesterolemia, arh, cholesterol, protein binding-protein transport complex, protein binding/protein transport
• 由来する生物種: Rattus norvegicus (rat); 詳細
• 細胞内の位置: Cytoplasm : D3ZAR1; Cell membrane ; Single-pass type I membrane protein : P01130
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16907.69

構造登録者

Dvir, H.,Zajonc, D.M. (登録日: 2011-06-29, 公開日: 2012-04-18, 最終更新日: 2024-02-28)

主引用文献

Dvir, H.,Shah, M.,Girardi, E.,Guo, L.,Farquhar, M.G.,Zajonc, D.M.
Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail.
Proc.Natl.Acad.Sci.USA, 109:6916-6921, 2012

PubMed Abstract: Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY(0) internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I(-7)xF(-5)xNPxY(0)QK(+2). The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y(0)). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y(0) explains the distinctive ability of ARH to internalize proteins containing either FxNPxY(0) or FxNPxF(0) sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.

PubMed: 22509010
DOI: 10.1073/pnas.1114128109

実験手法

X-RAY DIFFRACTION (1.37 Å)