Document Detail


Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail.
MedLine Citation:
PMID:  22509010     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hay Dvir; Mehul Shah; Enrico Girardi; Lixia Guo; Marilyn G Farquhar; Dirk M Zajonc
Publication Detail:
Type:  In Vitro; Journal Article     Date:  2012-04-16
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-02     Completed Date:  2012-07-10     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6916-21     Citation Subset:  IM    
Affiliation:
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/3SO6
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / chemistry*,  genetics,  metabolism
Amino Acid Sequence
Animals
Atherosclerosis / etiology,  genetics,  metabolism
Cholesterol, LDL / metabolism
Crystallography, X-Ray
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Hypercholesterolemia / etiology,  genetics,  metabolism
Models, Molecular
Molecular Sequence Data
Multiprotein Complexes
Mutation
Protein Interaction Domains and Motifs
Protein Stability
Protein Structure, Secondary
Rats
Receptors, LDL / chemistry*,  genetics,  metabolism
Recombinant Proteins / chemistry,  genetics,  metabolism
Sequence Homology, Amino Acid
Static Electricity
Grant Support
ID/Acronym/Agency:
R37 DK017724/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Cholesterol, LDL; 0/LDLRAP1 protein, human; 0/Multiprotein Complexes; 0/Receptors, LDL; 0/Recombinant Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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