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조회1,059

Columbia University College of Physicians and Surgeons

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J. Biol. Chem., First Published on August 11, 2003, doi: 10.1074/jbc.M306028200 Regulated Intramembrane Proteolysis of the p75 Neurotrophin Receptor Modulates Its Association with the TrkA Receptor

Abstract

Kwang-Mook Jung^‡, Serena Tan^‡, Natalie Landman^‡, Kseniya Petrova^‡, Simon Murray^§, Renee Lewis^‡, Peter K. Kim^‡, Dae Sup Kim^¶, Sung Ho Ryu^¶, Moses V. Chao^§ and Tae-Wan Kim^‡¶∥

^‡Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, the ^§Molecular Neurobiology Program, Skirball Institute, New York University Medical Center, New York, New York 10016, and the ^¶Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea

^∥ To whom correspondence should be addressed: Dept. of Pathology, Columbia University, P&S 14-442, New York, NY 10032.

Abstract
The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent γ-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including β-amyloid precursor protein (APP) and Notch. A small fraction of intracellular domains derived from both APP and Notch translocates to and appears to function in the nucleus, suggesting a generic role for γ-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75^NTR) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75^NTR is a multifunctional type I membrane protein that promotes neurotrophin-induced neuronal survival and differentiation by forming a heteromeric co-receptor complex with the Trk receptors. Mass spectrometric analysis revealed that γ-secretase-mediated cleavage of p75^NTR occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid β-peptide 40 (Aβ40) cleavage of APP and is topologically distinct from the major TM cleavage site of Notch 1. Size exclusion chromatography and co-immunoprecipitation analyses revealed that TrkA forms a molecular complex together with either full-length p75 or membrane-tethered C-terminal fragments. The p75-ICD was not recruited into the TrkA-containing high molecular weight complex, indicating that γ-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that γ-secretase-mediated p75^NTR proteolysis plays a role in the formation/disassembly of the p75-TrkA receptor complex by regulating the availability of the p75 TM domain that is required for this interaction.

논문정보

형식Research article
게재일2003년 10월 (BRIC 등록일 )
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학
피인용횟수120회 이상 인용된 논문

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