Constitutive cleavage of the single-pass transmembrane protein alcadein? prevents aberrant peripheral retention of Kinesin-1.

ABSTRACT: Various membrane proteins are shed by proteinases, constitutively and/or when stimulated by external signals. While the physiological significance of external signal-induced cleavages has been intensely investigated, relatively little is known about the function of constitutive cleavages. Alcadein? (Alc?; also called Calsyntenin-1) is an evolutionarily conserved type I single-pass transmembrane protein that binds to kinesin-1 light chain (KLC) to activate kinesin-1's transport of Alc?-containing vesicles. We found that Alc? was constitutively and efficiently cleaved to liberate its ectodomain into the extracellular space, and that full-length Alc? protein was rarely detected on the cell surface. The secretion efficiency of the ectodomain was unaltered by a mutation that both abolished Alc?'s KLC-binding activity and attenuated its peripheral transport, suggesting that Alc?'s cleavage occurred, at least partly, en route to the cell surface. We further demonstrated that uncleavable mutant Alc? proteins readily accumulated on the cell surface and induced aberrant peripheral recruitment of KLC1 and kinesin heavy chain. Our observations suggest that Alc? is efficiently processed in part to minimize the inappropriate peripheral retention of kinesin-1. This role might exemplify the functional relevance of the constitutive cleavage of single-pass transmembrane proteins.

SUBMITTER: Maruta C 

PROVIDER: S-EPMC3414480 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature