Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor.
The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent gamma-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including beta-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 gamma-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75NTR) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75NTR 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 gamma-secretase-mediated cleavage of p75NTR occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid beta-peptide 40 (Abeta40) 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 gamma-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that gamma-secretase-mediated p75NTR 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.
Jung
Kwang-Mook
KM
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, NY 10032, USA.
Tan
Serena
S
Landman
Natalie
N
Petrova
Kseniya
K
Murray
Simon
S
Lewis
Renee
R
Kim
Peter K
PK
Kim
Dae Sup
DS
Ryu
Sung Ho
SH
Chao
Moses V
MV
Kim
Tae-Wan
TW
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D011233:Precipitin Tests; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020917:Receptor, trkA; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human