LAR-RPTPs: synaptic adhesion molecules that shape synapse development

Um, Ji Won; Ko, Jaewon

doi:10.1016/j.tcb.2013.07.004

Cited by 150 publications

(178 citation statements)

References 93 publications

Supporting

Mentioning

175

Contrasting

Order By: Relevance

“…Discussion LAR-RPTPs were originally identified as essential elements for early neuron development, but they have recently emerged as synaptic adhesion molecules 2,3 . Previous structural studies of LAR-RPTPs focused on the Ig domains 17,28 and catalytic phosphatase domains 29 , and provided insights into the arrangement of the Ig domains, the proteoglycan-mediated clustering of the Ig domains and the role of the two tandem phosphatase domains.…”

Section: Minimal Domain Identification For Binding and Synaptogenesismentioning

confidence: 99%

“…The leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs), which are classified as type IIa RPTPs, have recently emerged as a major family of synaptic adhesion molecules that also play crucial roles in neurite outgrowth, axon guidance and central nervous system (CNS) regeneration 2,3 . The vertebrate LAR-RPTP family has three members, LAR, PTPd and PTPs; their extracellular regions contain three immunoglobulin-like (Ig) domains and four to eight fibronectin III (FNIII) repeats (determined by alternative splicing).…”

mentioning

confidence: 99%

“…The LARRPTPs have a single transmembrane domain followed by two intracellular phosphatase domains (a membrane-proximal catalytic domain called D1 and a membrane-distal non-catalytic domain called D2) where multiple intracellular adaptor proteins bind 6 . Recently, a growing number of postsynaptic adhesion molecules have been identified as adhesion partners of the LAR-RPTPs; these include NGL-3 (netrin-G ligand 3), TrkC (neurotrophin receptor tyrosine kinase C), IL-1RAcP (interleukin 1 receptor accessory protein), IL1RAPL1 (IL-1 receptor accessory protein-like 1) and the Slitrks (Slit-and Trk-like family proteins) 2,3 . Two alternative splicing sites within the Ig domain of the LAR-RPTPs (MeA and MeB) have received particular attention, because they modulate the interactions with various postsynaptic ligands, such as TrkC, IL-1RAcP and IL1RAPL1 (refs 7-9).…”

mentioning

confidence: 99%

“…However, the lack of a high-resolution structure of the LAR-RPTP/Slitrk complex has limited our understanding of how these proteins act in synapse formation. Developing a greater understanding of the detailed molecular mechanisms underlying the functions of trans-synaptic adhesion pathways will be crucial for the future development of therapeutic strategies against a range of neurological disorders in which Slitrks and LAR-RPTPs have been implicated, including autism spectrum disorders, attention-deficit hyperactivity disorders, Tourette's syndrome, trichotillomania and epilepsy 2,3,13 .…”

mentioning

confidence: 99%

See 3 more Smart Citations

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

et al. 2014

Self Cite

View full text Add to dashboard Cite

Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit-and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structureguided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.

show abstract

Section: Minimal Domain Identification For Binding and Synaptogenesismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The leukocyte common antigenrelated receptor protein tyrosine phosphatases (LAR-RPTPs), which comprise three members in vertebrates (LAR, PTPδ, and PTPσ), have recently emerged as synapse organizers (3). They mediate presynaptic differentiation via various postsynaptic ligands (3).…”

mentioning

confidence: 99%

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Pramanik

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Leukocyte common antigen-related receptor protein tyrosine phosphatases-comprising LAR, PTPδ, and PTPσ-are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding-defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.PTPσ | glypican | LRRTM4 | synaptic cell adhesion | heparan sulfate

show abstract

Trans‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules

Kim

Wulschner

et al. 2022

BioEssays

Self Cite

View full text Add to dashboard Cite

Bidirectional trans‐synaptic signaling is essential for the formation, maturation, and plasticity of synaptic connections. Synaptic cell adhesion molecules (CAMs) are prime drivers in shaping the identities of trans‐synaptic signaling pathways. A series of recent studies provide evidence that diverse presynaptic cell adhesion proteins dictate the regulation of specific synaptic properties in postsynaptic neurons. Focusing on mammalian synaptic CAMs, this article outlines several exemplary cases supporting this notion and highlights how these trans‐synaptic signaling pathways collectively contribute to the specificity and diversity of neural circuit architecture.

show abstract

LAR-RPTPs: synaptic adhesion molecules that shape synapse development

Cited by 150 publications

References 93 publications

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Trans‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules

Contact Info

Product

Resources

About