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Biophysical Reviews

, Volume 10, Issue 2, pp 481–492 | Cite as

How multi-scale structural biology elucidated context-dependent variability in ectodomain conformation along with the ligand capture and release cycle for LDLR family members

  • Terukazu Nogi
Review

Abstract

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.

Keywords

Low-density lipoprotein receptor Endocytosis Conformational change X-ray crystallography Molecular recognition 

Notes

Acknowledgements

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.

Compliance with ethical standards

Conflict of interest

Terukazu Nogi declares that he has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.

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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Graduate School of Medical Life ScienceYokohama City UniversityYokohamaJapan

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