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Molecular and Cellular Biology, June 2007, p. 4121-4132, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01708-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Combinatorial Expression of {alpha}- and {gamma}-Protocadherins Alters Their Presenilin-Dependent Processing{triangledown}

Stefan Bonn, Peter H. Seeburg,* and Martin K. Schwarz

Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany

Received 11 September 2006/ Returned for modification 27 November 2006/ Accepted 19 March 2007

{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.

* Corresponding author. Mailing address: Dept. of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany. Phone: 49-6221-486-495. Fax: 49-6221-486-110. E-mail: seeburg{at}mpimf-heidelberg.mpg.de

{triangledown} Published ahead of print on 2 April 2007.

Molecular and Cellular Biology, June 2007, p. 4121-4132, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01708-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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