Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11.
SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of the amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results in sequestration of APP in the Golgi and in protection from processing into the amyloid-beta peptide (Abeta), the principal component of senile plaques in Alzheimer's disease (AD). To gain insight into the molecular mechanisms governing sorLA and APP interaction, we have dissected the respective protein interacting domains. Using a fluorescence resonance energy transfer (FRET) based assay of protein proximity, we identified binding sites in the extracellular regions of both proteins. Fine mapping by surface plasmon resonance analysis and analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex with the carbohydrate-linked domain of APP. These data shed new light on the molecular determinants of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque formation in patients with AD.
Andersen
Olav M
OM
Max-Delbrueck-Center for Molecular Medicine, Berlin, 13125 Berlin, Germany. o.andersen@mdc-berlin.de
Schmidt
Vanessa
V
Spoelgen
Robert
R
Gliemann
Jørgen
J
Behlke
Joachim
J
Galatis
Denise
D
McKinstry
William J
WJ
Parker
Michael W
MW
Masters
Colin L
CL
Hyman
Bradley T
BT
Cappai
Roberto
R
Willnow
Thomas E
TE
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics / Q000502:physiology*; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human