Characterization of the VPS10 domain of SorLA/LR11 as binding site for the neuropeptide HA.
The single transmembrane receptor sorLA/LR11 contains binding domains typical for the low-density lipoprotein receptors and a VPS10 domain which, in the related receptor sortilin, binds the neuropeptide neurotensin. SorLA is synthesized as a proreceptor which is processed to the mature form by a furin-like propeptidase. Endogenous sorLA and its hydra homologue HAB bind the neuropeptide head activator (HA). Transiently expressed partial sorLA constructs were investigated for ligand binding. We found that HA binds with nanomolar affinity to the VPS10 domain. The sorLA propeptide also bound to the VPS10 domain, whereas the receptor-associated protein RAP interacted both with the class A repeats and the VPS10 domain. The sorLA propeptide inhibited binding of HA to full-length sorLA and to the VPS10 domain. It also interfered with binding of HA to hydra HAB, which is taken as evidence for a highly conserved tertiary structure of the VPS10 domains of this receptor in hydra and mammals. The propeptide inhibited HA-stimulated mitosis and proliferation in the human neuroendocrine cell line BON and the neuronal precursor cell line NT2. We conclude that sorLA is necessary for HA signaling and function.
Lintzel
Julia
J
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistr. 52, D-20246 Hamburg, Germany.
Franke
Inga
I
Riedel
I Björn
IB
Schaller
H Chica
HC
Hampe
Wolfgang
W
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D006801:Humans; D007150:Immunohistochemistry; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D008938:Mitosis / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D011973:Receptors, LDL; C102582:SORL1 protein, human; C032522:head activator peptide; D011761:Pyrrolidonecarboxylic Acid