Liprin-α-Mediated Assemblies and Their Roles in Synapse Formation

Abstract

Brain’s functions, such as memory and learning, rely on synapses that are highly specialized cellular junctions connecting neurons. Functional synapses orchestrate the assembly of ion channels, receptors, enzymes, and scaffold proteins in both pre- and post-synapse. Liprin-α proteins are master scaffolds in synapses and coordinate various synaptic proteins to assemble large protein complexes. The functions of liprin-αs in synapse formation have been largely uncovered by genetic studies in diverse model systems. Recently, emerging structural and biochemical studies on liprin-α proteins and their binding partners begin to unveil the molecular basis of the synaptic assembly. This review summarizes the recent structural findings on liprin-αs, proposes the assembly mechanism of liprin-α-mediated complexes, and discusses the liprin-α-organized assemblies in the regulation of synapse formation and function.

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy and periventricular calcifications

“…7,42–44 Liprin-α proteins function as major scaffold proteins at the presynaptic active zone and at the postsynaptic density and also play a role in intracellular transport, cell motility and protein assembly. 3,5,6,45–47 Wei et al . found that liprin-α2 forms a ternary complex simultaneously binding liprin-β1 and CASK, another presynaptic scaffold protein, supporting the hypothesis that liprin-β1 could act as a core scaffold and mediate large protein assemblies in the presynaptic active zone.…”

“…1,4 Liprin-α proteins are major scaffold proteins involved in synapse formation, synaptic signaling and axonal transport processes via the assembly of large protein complexes. 5,6 Although yet to be confirmed, it has been suggested, that liprin-β1 could play a role in the regulation of liprin-α mediated protein assemblies. 1,6,7 In line with this is the observation that liprin-β1 forms a ternary complex with liprin-α2 and CASK, 3 a presynaptic scaffolding protein essential for neurodevelopment.…”

“…5,6 Although yet to be confirmed, it has been suggested, that liprin-β1 could play a role in the regulation of liprin-α mediated protein assemblies. 1,6,7 In line with this is the observation that liprin-β1 forms a ternary complex with liprin-α2 and CASK, 3 a presynaptic scaffolding protein essential for neurodevelopment. 8,9 A previous knock-out model of the PPFIBP1 homolog hlb-1 in C. elegans showed abnormal locomotion behavior.…”

Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

“…Liprin-α proteins from various species form condensates in cells through a process termed liquid-liquid phase separation (LLPS) (Emperador-Melero et al ., 2021; Liang et al ., 2021; McDonald et al , 2020; Xie et al ., 2021). During LLPS, proteins form dynamic, non-membrane surrounded compartments through demixing from the diffuse state out of the cytosol (Bracha et al , 2019).…”

“…Upon CASK binding, a long α-helical segment (αN-segment in Figs. 1, 5) immediately N-terminal to the SAM domains of Liprin-α performs a significant outward turn (Wei et al ., 2011; Xie et al ., 2021). As the αN-segment is close in sequence to the intrinsically disordered region (IDR), it is conceivable that this movement of αN alters the propensity of the IDR to condensate and induce phase separation.…”