Structural basis of dynamic glycine receptor clustering by gephyrin.

M. Sola (1) , Vn Bavro (1) , Joanna Timmins (1) , T. Franz (1) , S. Ricard-Blum (1) , G. Schoehn (1) , Rw Ruigrok (1) , I. Paarmann (1) , T. Saiyed (1) , Ga O'Sullivan (1) , B. Schmitt (1) , H. Betz (1) , W. Weissenhorn (1)

1 IBCP - Institut de biologie et chimie des protéines [Lyon]

Gephyrin is a bi-functional modular protein involved in molybdenum cofactor biosynthesis and in postsynaptic clustering of inhibitory glycine receptors (GlyRs). Here, we show that full-length gephyrin is a trimer and that its proteolysis in vitro causes the spontaneous dimerization of its C-terminal region (gephyrin-E), which binds a GlyR beta-subunit-derived peptide with high and low affinity. The crystal structure of the tetra-domain gephyrin-E in complex with the beta-peptide bound to domain IV indicates how membrane-embedded GlyRs may interact with subsynaptic gephyrin. In vitro, trimeric full-length gephyrin forms a network upon lowering the pH, and this process can be reversed to produce stable full-length dimeric gephyrin. Our data suggest a mechanism by which induced conformational transitions of trimeric gephyrin may generate a reversible postsynaptic scaffold for GlyR recruitment, which allows for dynamic receptor movement in and out of postsynaptic GlyR clusters, and thus for synaptic plasticity.Gephyrin is a bi-functional modular protein involved in molybdenum cofactor biosynthesis and in postsynaptic clustering of inhibitory glycine receptors (GlyRs). Here, we show that full-length gephyrin is a trimer and that its proteolysis in vitro causes the spontaneous dimerization of its C-terminal region (gephyrin-E), which binds a GlyR beta-subunit-derived peptide with high and low affinity. The crystal structure of the tetra-domain gephyrin-E in complex with the beta-peptide bound to domain IV indicates how membrane-embedded GlyRs may interact with subsynaptic gephyrin. In vitro, trimeric full-length gephyrin forms a network upon lowering the pH, and this process can be reversed to produce stable full-length dimeric gephyrin. Our data suggest a mechanism by which induced conformational transitions of trimeric gephyrin may generate a reversible postsynaptic scaffold for GlyR recruitment, which allows for dynamic receptor movement in and out of postsynaptic GlyR clusters, and thus for synaptic plasticity.

Domaines: Biochimie, Biologie Moléculaire

M. Sola, Vn Bavro, Joanna Timmins, T. Franz, S. Ricard-Blum, et al.. Structural basis of dynamic glycine receptor clustering by gephyrin.. EMBO Journal, 2004, 23, pp.2510-2519. ⟨hal-00313935⟩