How multi-scale structural biology elucidated context-dependent variability in ectodomain conformation along with the ligand capture and release cycle for LDLR family members
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The low-density lipoprotein receptor (LDLR) and its homologs capture and internalize lipoproteins into the cell. Due to the fact that LDLR family members possess a modular ectodomain that undergoes dynamic conformational changes, multi-scale structural analysis has been performed so as to understand the ligand capture and release mechanism. For example, crystallographic analyses have provided models for both the entire ectodomain and high-resolution structures of individual modules. In addition, nuclear magnetic resonance spectroscopic analyses have shown the rigidity and flexibility of inter-module linkers to restrict the mobility of ectodomain. Accumulated structural data suggest that the ectodomains of LDLR family members are flexible at the cell surface and switch between two metastable conformations, that is, the extended and contracted conformations. Recent structural analysis of ApoER2, a close homolog of LDLR, raised the possibility that the receptor binds with the ligand in the contracted conformation. After transport to an endosome by endocytosis, the receptor undergoes a conformational change to the closed conformation for completion of ligand release. In contrast, LDLR has been reported to adopt the extended conformation when it binds with a inhibitory regulator that recruits LDLR toward the degradation pathway. These findings support a mechanism of different ectodomain conformations for binding the ligand versus binding the regulatory protein. In this review, I provide an overview of studies that analyze the structural and biophysical properties of the ectodomains of LDLR family members and discuss a hypothetical model for ligand uptake and receptor recycling that integrates the known ectodomain conformational variability.
KeywordsLow-density lipoprotein receptor Endocytosis Conformational change X-ray crystallography Molecular recognition
The author would like to congratulate Prof. Fumio Arisaka on the occasion of his 70th birthday and thank him for his long-standing contributions in the development and promulgation of biophysical methods. The author thanks Samuel Thompson for editing the manuscript and Prof. Junichi Takagi for useful discussions.
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Conflict of interest
Terukazu Nogi declares that he has no conflicts of interest.
This article does not contain any studies with human participants or animals performed by the author.
- Cheng Z, Biechele T, Wei Z et al (2011) Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat Struct Mol Biol 18:1204–1210. https://doi.org/10.1038/nsmb.2139
- Day IN, Whittall RA, O’Dell SD et al (1997) Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat 10:116–127. https://doi.org/10.1002/(SICI)1098-1004(1997)10:2<116::AID-HUMU4>3.0.CO;2-I
- Hirai H, Yasui N, Yamashita K et al (2017) Structural basis for ligand capture and release by the endocytic receptor ApoER2. EMBO Rep 18:982–999. https://doi.org/10.15252/embr.201643521
- Lo Surdo P, Bottomley MJ, Calzetta A et al (2011) Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep 12:1300–1305. https://doi.org/10.1038/embor.2011.205
- Sun XM, Patel DD, Webb JC et al (1994) Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype. Arterioscler Thromb 14:85–94Google Scholar
- Yamamoto T, Davis CG, Brown MS et al (1984) The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39:27–38Google Scholar
- Yasui N, Nogi T, Kitao T, Nakano Y, Hattori M, Takagi J (2007) Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors. Proc Natl Acad Sci USA 104:9988–9993. https://doi.org/10.1073/pnas.0700438104 CrossRefPubMedPubMedCentralGoogle Scholar
- Zong Y, Zhang B, Gu S et al (2012) Structural basis of agrin-LRP4-MuSK signaling. Genes Dev 26:247–258. https://doi.org/10.1101/gad.180885.111