An alternative amino-terminus expressed in the central nervous system converts agrin to a type II transmembrane protein

Agrin is a basal lamina-associated heparansulfate proteoglycan that is a ke y molecule in the formation of the vertebrate neuromuscular junction. The c arboxy-terminal part of agrin is involved in its synaptogenic activity. The aminoterminal end of chick agrin consists of a signal sequence, required f or the targeting of the protein to the secretory pathway, and the amino-ter minal agrin (NtA) domain that binds to basal lamina-associated laminins. Th e cDNA encoding rat agrin lacks this NtA domain and instead codes for a sho rter amino-terminal end. While the NtA domain is conserved in several speci es, including human, sequences homologous to the amino-terminus of rat agri n have not been described. In this work, we have characterized these aminot erminal sequences in mouse and chick. We show that they all serve as a nonc leaved signal anchor that immobilizes the protein in a N-cyto/C-exo orienta tion in the plasma membrane. Like the secreted form, this transmembrane for m of agrin is highly glycosylated indicative of a heparansulfate proteoglyc an. The structure of the 5' end of the mouse agrin gene suggests that a dis tinct promoter drives expression of the transmembrane form. Agrin transcrip ts encoding this form are enriched in the embryonic brain, particularly in neurons. To our knowledge, this is the first example of a molecule that is synthesized both as a basal lamina and a plasma membrane protein.