Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation

Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive‐compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction‐related effects, and the implications of these findings for the PTPRD‐associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

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“…SALMs, especially those that are products of the genes LRFN1 and ‐ 5 , can also serve as binding partners of DSF family members, including PTPRD …”

Section: What Is Ptprd?mentioning

confidence: 99%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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“…The binding interface in SALM3-PTPσ complex is formed by three interaction sites ( Fig. 4b, Supplementary Table S2), similar to SALM5-PTPδ (PDB 5XNP, 5XWT) 17,18 17 . Here, we generated mutations in SALM3 on these three sites (Fig 4b, c) in order to validate the SALM3 complex structure.…”

Section: Mutational Analysis Of Salm3-ptpσ Interfacementioning

confidence: 97%

“…Thus, we conclude that the dimerization mechanism through the LRR domains is conserved in the family, generating a unique dimeric post-synaptic 17,19 (see below), and SALM4 regulates the function of SALM3 by cis-inhibition, most likely through heterodimer formation 16 . Function of SALM2 remains unclear, but it appears to be able to bind the LAR-RPTP receptors 18 , whereas the function of SALM1 appears quite different, with reported involvement in actin mediated post-synaptic neurexin clustering, and no synapse formation activity reported 28 , and has much lower affinity (with K d ca. 50 μM) in vitro for the PTPσ (SK and TK, unpublished observations).…”

Section: Dimerization Through the Lrr Domain Is A Defining Feature Ofmentioning

confidence: 98%

“…The recent SALM5-PTPδ complex crystal structures at 3.7 Å and 4.2 Å resolution showed that the LRRCT-region and Ig-domain of SALM5 interact with the Ig2 and Ig3 domains of PTPδ, and the presence of meB sequence enhanced the interaction 17,18 . We also reported in our earlier study 19 using surface plasmon resonance (SPR) that the interaction of SALM3 and PTPσ is enhanced by ten-fold in presence of meB.…”

Section: Mutational Analysis Of Salm3-ptpσ Interfacementioning

confidence: 99%

“…Crystal structures of human SALM5-PTPδ, and also SALM2-PTPδ show a 2:2 heterotetrameric trans-synaptic complexes 17,18 . We previously reported the crystal structure of mouse SALM5 LRR-Ig domain and solution structures of SALM3 and SALM5 extracellular regions 19 .…”

Section: Introductionmentioning

confidence: 98%

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Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

Karki

Shkumatov

Bae

et al. 2020

Preprint

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Synaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase σ (PTPσ). We solved the crystal structure of the dimerized leucine rich repeat (LRR) domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTPσ using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays.Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTPσ complex to exert synaptogenic activity.

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LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

et al. 2022

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LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian‐specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism‐susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone‐3‐lysine‐9‐associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male‐restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%–26% lower than expected from Hardy–Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild‐type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. Lay Summary LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher‐functioning autism is more common in males than females.

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Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation

Cited by 34 publications

References 41 publications

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

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