Structures of LRP2 reveal a molecular machine for endocytosis.

Autor:	Beenken A; Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Cerutti G; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA., Brasch J; Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA., Guo Y; Aaron Diamond AIDS Research Center, Columbia University, New York, NY 10032, USA., Sheng Z; Aaron Diamond AIDS Research Center, Columbia University, New York, NY 10032, USA., Erdjument-Bromage H; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA., Aziz Z; Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA., Robbins-Juarez SY; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Chavez EY; Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA., Ahlsen G; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA., Katsamba PS; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA., Neubert TA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016, USA., Fitzpatrick AWP; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: anthony.fitzpatrick@columbia.edu., Barasch J; Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Columbia University George M. O'Brien Urology Center, New York, NY 10032, USA. Electronic address: jmb4@columbia.edu., Shapiro L; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: lss8@columbia.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Feb 16; Vol. 186 (4), pp. 821-836.e13. Date of Electronic Publication: 2023 Feb 06.
DOI:	10.1016/j.cell.2023.01.016
Abstrakt:	The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu