Combinatorial expression of alpha- and gamma-protocadherins alters their presenilin-dependent processing.
Alpha- and gamma-protocadherins (Pcdhs) are type I transmembrane receptors expressed predominantly in the central nervous system and located in part in synapses. They are transcribed from complex genomic loci, giving rise in the mouse to 14 alpha-Pcdh and 22 gamma-Pcdh isoforms consisting of variable domains, each encompassing the extracellular region, the transmembrane region, and part of the intracellular region harboring the alpha- or gamma-Pcdh-specific invariant cytoplasmic domain. Presenilin-dependent intramembrane proteolysis (PS-IP) of gamma-Pcdhs and the formation of alpha/gamma-Pcdh heteromers led us to investigate the effects of homo- and heteromer formation on gamma- and putative alpha-Pcdh membrane processing and signaling. We find that upon surface delivery, alpha-Pcdhs, like gamma-Pcdhs, are subject to matrix metallo-protease cleavage followed by PS-IP in neurons. We further demonstrate that the combinatorial expression of alpha- and gamma-Pcdhs modulates the extent of their PS-IP, indicating the formation of alpha/gamma-Pcdh heteromers with an altered susceptibility to processing. Cell-specific expression of alpha/gamma-Pcdh isoforms could thus determine cell and synapse adhesive properties as well as intracellular and nuclear signaling by their soluble cytoplasmic cleavage products, alpha C-terminal fragment 2 (alpha-CTF-2) and gamma-CTF-2.
Bonn
Stefan
S
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
Seeburg
Peter H
PH
Schwarz
Martin K
MK
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D000091363:Protocadherins; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism
D000070585:Cadherin Related Proteins; D015820:Cadherins; D015816:Cell Adhesion Molecules, Neuronal; C464785:Gamma-protocadherins; D008565:Membrane Proteins; D009479:Neuropeptides; C113143:Pcdha4 protein, mouse; D053763:Presenilins; D020033:Protein Isoforms; D000091363:Protocadherins; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse