Combinatorial Expression of α- and γ-Protocadherins Alters Their Presenilin-Dependent Processing

Abstract

ABSTRACT α- and γ-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 α-Pcdh and 22 γ-Pcdh isoforms consisting of variable domains, each encompassing the extracellular region, the transmembrane region, and part of the intracellular region harboring the α- or γ-Pcdh-specific invariant cytoplasmic domain. Presenilin-dependent intramembrane proteolysis (PS-IP) of γ-Pcdhs and the formation of α/γ-Pcdh heteromers led us to investigate the effects of homo- and heteromer formation on γ- and putative α-Pcdh membrane processing and signaling. We find that upon surface delivery, α-Pcdhs, like γ-Pcdhs, are subject to matrix metallo-protease cleavage followed by PS-IP in neurons. We further demonstrate that the combinatorial expression of α- and γ-Pcdhs modulates the extent of their PS-IP, indicating the formation of α/γ-Pcdh heteromers with an altered susceptibility to processing. Cell-specific expression of α/γ-Pcdh isoforms could thus determine cell and synapse adhesive properties as well as intracellular and nuclear signaling by their soluble cytoplasmic cleavage products, α C-terminal fragment 2 (α-CTF-2) and γ-CTF-2.