Interplay Between Phosphorylation and Palmitoylation Mediates Plasma Membrane Targeting and Sorting of GAP43

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2014 Aug 29

PMID 25165142

Citations 22

Authors

Anne Gauthier-Kemper

Maxim Igaev

Frederik Sundermann

Dennis Janning

Jorg Bruhmann

Katharina Moschner

Hans-Jurgen Reyher

Wolfgang Junge

Konstantin Glebov

Jochen Walter

Lidia Bakota

Roland Brandt

Affiliations

Soon will be listed here.

Abstract

Phosphorylation and lipidation provide posttranslational mechanisms that contribute to the distribution of cytosolic proteins in growing nerve cells. The growth-associated protein GAP43 is susceptible to both phosphorylation and S-palmitoylation and is enriched in the tips of extending neurites. However, how phosphorylation and lipidation interplay to mediate sorting of GAP43 is unclear. Using a combination of biochemical, genetic, and imaging approaches, we show that palmitoylation is required for membrane association and that phosphorylation at Ser-41 directs palmitoylated GAP43 to the plasma membrane. Plasma membrane association decreased the diffusion constant fourfold in neuritic shafts. Sorting to the neuritic tip required palmitoylation and active transport and was increased by phosphorylation-mediated plasma membrane interaction. Vesicle tracking revealed transient association of a fraction of GAP43 with exocytic vesicles and motion at a fast axonal transport rate. Simulations confirmed that a combination of diffusion, dynamic plasma membrane interaction and active transport of a small fraction of GAP43 suffices for efficient sorting to growth cones. Our data demonstrate a complex interplay between phosphorylation and lipidation in mediating the localization of GAP43 in neuronal cells. Palmitoylation tags GAP43 for global sorting by piggybacking on exocytic vesicles, whereas phosphorylation locally regulates protein mobility and plasma membrane targeting of palmitoylated GAP43.

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