Affinage

CASKIN1

Caskin-1 · UniProt Q8WXD9

Length
1431 aa
Mass
149.8 kDa
Annotated
2026-06-09
20 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASKIN1 is a multidomain neuronal scaffold protein that organizes synaptic protein complexes and contributes to dendritic spine architecture and synaptic plasticity (PMID:31727973). It engages the core synaptic scaffold CASK through a short EEIWVLRK peptide motif that binds the CASK CaMK domain and competes with a homologous Mint1 motif for the same site, establishing mutually exclusive CASK complexes (PMID:21763699). CASKIN1 self-assembles through SAM-domain-mediated homopolymerization (PMID:21805519), an oligomeric state that SASH1 disrupts via a heterogeneous SAM-SAM interaction at the end-helix/mid-loop interface (PMID:39688081). Its atypical SH3 domain lacks the aromatic residues that form the canonical proline-rich binding groove and instead selectively binds lysophosphatidic acid, as established by NMR structure and lipid-binding assays (PMID:28104445, PMID:33467043). CASKIN1 is recruited to the EphB1 receptor tyrosine kinase via the adaptor Nck, which couples a phosphotyrosine on EphB1 to the CASKIN1 proline-rich region and triggers phosphorylation of its SH3 domain at Y296/Y336 with attendant conformational change (PMID:23181695). Postsynaptically, CASKIN1 is enriched in dendritic spine heads, associates with Shank2, and promotes mushroom spine formation, with combined loss of Caskin1 and Caskin2 impairing LTP, altering AMPA receptor phosphorylation, and causing spatial memory and novelty-recognition deficits (PMID:31727973); at hippocampal glutamatergic synapses CASKIN1 plays a secondary, redundant role relative to CASKIN2 in synaptic transmission (PMID:41223222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2011 High

    Defined how CASKIN1 docks onto the central synaptic scaffold CASK and why this is exclusive with Mint1, explaining competitive assembly of CASK complexes.

    Evidence Peptide binding assays and site-directed mutagenesis of the CASK CaMK-domain binding site in vitro

    PMID:21763699

    Open questions at the time
    • Affinity and stoichiometry in a full-length cellular context not established
    • Functional consequence of CASK-Mint1-Caskin1 competition at synapses not demonstrated
  2. 2011 Medium

    Established that the CASKIN1 SAM domain self-associates into higher-order homopolymers, defining a structural basis for scaffold clustering.

    Evidence Native gel screen with negGFP-SAM fusions and electron microscopy

    PMID:21805519

    Open questions at the time
    • Polymer geometry and physiological regulation not resolved
    • Screening study with limited Caskin1-specific depth
  3. 2012 Medium

    Showed CASKIN1 is an EphB1 receptor signaling effector, recruited through Nck and post-translationally modified in a way that remodels its SH3 domain.

    Evidence Reciprocal co-immunoprecipitation, mass-spectrometry phosphosite mapping, and CD spectroscopy

    PMID:23181695

    Open questions at the time
    • Downstream signaling output of Y296/Y336 phosphorylation not defined
    • Single lab; in vivo relevance of EphB1-Nck-Caskin1 axis untested
  4. 2014 Medium

    Demonstrated CASKIN1 marks only a subset of CASK-positive synapses, implying specialized rather than universal synaptic functions.

    Evidence Immunohistochemistry and subcellular fractionation in bovine retina

    PMID:25123431

    Open questions at the time
    • No functional consequence demonstrated
    • Molecular determinant of selective synaptic targeting unknown
  5. 2017 Medium

    Reassigned the CASKIN1 SH3 domain function from a protein-interaction module to a lipid sensor by showing selective high-affinity binding to lysophosphatidic acid.

    Evidence In vitro lipid-binding assays and structural analysis of the binding interface

    PMID:28104445

    Open questions at the time
    • Cellular role of LPA binding not established
    • No proline-rich protein ligand identified
  6. 2018 Medium

    Established CASKIN1 as a CNS-wide synaptic protein with defined behavioral functions in nociception, anxiety, fear, and spatial memory.

    Evidence Caskin1-knockout mice, behavioral test battery, immunohistochemistry, fractionation

    PMID:30359304

    Open questions at the time
    • Circuit and synaptic mechanism underlying behaviors not resolved
    • Single lab
  7. 2019 High

    Localized CASKIN1 to the postsynaptic spine head and linked it mechanistically to spine morphology, AMPA receptor regulation, and LTP via association with Shank2.

    Evidence Caskin1/2 double-knockout mice, LTP recordings, co-IP, immunocytochemistry, ultrastructure, and overexpression in cultured neurons

    PMID:31727973

    Open questions at the time
    • Caskin1-specific versus Caskin2-shared contribution not separated
    • Mechanism linking Shank2 binding to AMPA receptor phosphorylation unresolved
  8. 2021 High

    Provided the atomic-resolution basis for why the CASKIN1 SH3 domain cannot bind proline-rich motifs and confirmed a distinct LPA binding site.

    Evidence Solution NMR structure determination of the human Caskin1 SH3 domain

    PMID:33467043

    Open questions at the time
    • In vivo LPA engagement not demonstrated
    • Functional impact of Y296/Y336 phosphorylation on the structure not directly resolved here
  9. 2024 High

    Identified SASH1 as a regulator that disassembles CASKIN1 SAM homopolymers through a heterogeneous SAM-SAM interaction, defining a mechanism for controlling scaffold oligomerization.

    Evidence Yeast two-hybrid, SEC, ITC, GST pulldown, co-IP, TEM, sedimentation, mutagenesis guided by AlphaFold2 models, and immunofluorescence

    PMID:39688081

    Open questions at the time
    • Physiological context and neuronal consequence of SASH1-driven depolymerization not established
    • Regulatory triggers for the interaction unknown
  10. 2025 Medium

    Resolved the relative contribution of CASKIN1 at glutamatergic synapses, showing it is dispensable for synaptic transmission and redundant with the dominant CASKIN2.

    Evidence Conditional knockout mice with electrophysiology and synaptic transmission assays

    PMID:41223222

    Open questions at the time
    • CASKIN1-specific role at non-glutamatergic or peripheral synapses untested
    • Negative finding embedded in a CASKIN2-focused study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CASKIN1's distinct modules — CASK binding, SAM polymerization, LPA-sensing SH3, and EphB1/Nck phosphorylation — are integrated into a single regulated signaling event at the synapse remains unknown.
  • No unified model linking lipid binding, phosphorylation, and polymer state
  • Cellular trigger and consequence of SASH1-mediated depolymerization in neurons undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 1
Partners
CASKEPHB1NCKSASH1SHANK2

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 A short linear EEIWVLRK peptide motif from Caskin1 is necessary and sufficient for binding the CASK calmodulin kinase domain. This motif competes with a related peptide from Mint1 (EPIWVMRQ) for the same conserved binding site on CASK, explaining how Caskin1 and Mint1 form mutually exclusive competing complexes with CASK. Peptide binding assays, site-directed mutagenesis of CASK binding site, in vitro binding experiments Journal of molecular biology High 21763699
2011 The SAM domain of Caskin1 forms homopolymers, as identified by a native gel screen using negGFP-SAM fusions and confirmed by electron microscopy. Native gel electrophoresis with negGFP-SAM fusions, electron microscopy Protein science : a publication of the Protein Society Medium 21805519
2012 EphB1 receptor tyrosine kinase recruits Caskin1 through the adaptor protein Nck: Nck's SH2 domain binds to a phosphotyrosine on EphB1, while Nck's SH3 domains interact with the proline-rich domain of Caskin1. Complex formation results in tyrosine phosphorylation of the Caskin1 SH3 domain at tyrosines Y296 and Y336, which causes significant structural changes in the SH3 domain as measured by CD spectroscopy. Co-immunoprecipitation, mass spectrometry (phosphosite identification), CD spectroscopy Cell communication and signaling : CCS Medium 23181695
2014 Caskin1 localizes to a subset of CASK-positive synapses in the bovine retina, distinct from CASK which is present in virtually all retinal synapses; Caskin1 is enriched at only a subset of ribbon and conventional synapses, suggesting specialized rather than universal synaptic functions. Immunohistochemistry, fractionation/subcellular localization in bovine retina Molecular and cellular neurosciences Medium 25123431
2017 The atypical SH3 domain of human Caskin1 selectively binds lysophosphatidic acid (LPA) in vitro, with nanomolar affinity to LPA-containing membranous surfaces. The binding involves beta-strand residues distinct from the canonical proline-rich ligand-binding groove. No proline-rich protein interacting partner for this SH3 domain was identified. In vitro lipid-binding assays, NMR/structural analysis of binding interface Cellular signalling Medium 28104445
2018 Caskin1 localizes primarily at synapses throughout the brain and spinal cord. Caskin1-knockout mice exhibit enhanced nociception, anxiety-like behavior, increased fear conditioning, and impaired spatial memory, establishing that Caskin1 contributes to nociception, memory, and stress response in the CNS. Caskin1-KO mouse generation, comprehensive behavioral test battery, immunohistochemistry, biochemical fractionation Molecular brain Medium 30359304
2019 Caskin1 is enriched in dendritic spine heads postsynaptically and increases mushroom-shaped dendritic spine formation when overexpressed in hippocampal neurons. Caskin1 co-immunoprecipitates and co-localizes with the postsynaptic scaffold protein Shank2. Loss of Caskin proteins (double KO of Caskin1 and Caskin2) reduces synaptic profiles and dendritic spine area, impairs LTP, alters AMPA receptor phosphorylation, and causes deficits in novelty recognition and spatial memory. Double knockout mice, LTP recordings in hippocampal slices, immunoprecipitation, immunocytochemistry, ultrastructural analysis, overexpression in cultured neurons Scientific reports High 31727973
2021 Solution NMR structure of the human Caskin1 SH3 domain reveals that the canonical proline-rich peptide binding groove is absent due to missing key aromatic residues, supporting the conclusion that this SH3 domain does not bind proline-rich protein motifs. The LPA binding site is structurally distinct from the altered protein-binding groove. Solution NMR structure determination Cells High 33467043
2024 SASH1 was identified as a novel binding partner of Caskin1, interacting via SAM-SAM domain interaction at the end-helix (EH)/mid-loop (ML) interface. This heterogeneous SAM-SAM interaction disrupts Caskin1 tandem SAM homopolymers, as validated by sedimentation, TEM, co-IP, GST pulldown, and immunofluorescence. Key interface residues were identified by mutagenesis of AlphaFold2-predicted complex models. Yeast two-hybrid screening, size-exclusion chromatography, isothermal titration calorimetry, GST pulldown, co-immunoprecipitation, transmission electron microscopy, sedimentation assay, mutagenesis, immunofluorescence The FEBS journal High 39688081
2025 Conditional knockout analysis in mice showed that CASKIN1 (unlike CASKIN2) is not critical for synaptic transmission, synaptic strength, or AZ protein arrangement at glutamatergic synapses. Combined CASKIN1/2 deletion recapitulates CASKIN2-cKO phenotypes, indicating CASKIN1 plays a redundant or secondary role at hippocampal glutamatergic synapses compared to CASKIN2. Conditional knockout mice, electrophysiology, synaptic transmission assays Proceedings of the National Academy of Sciences of the United States of America Medium 41223222

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A human sterile alpha motif domain polymerizome. Protein science : a publication of the Protein Society 89 21805519
2011 The molecular basis of the Caskin1 and Mint1 interaction with CASK. Journal of molecular biology 35 21763699
2018 Distribution of Caskin1 protein and phenotypic characterization of its knockout mice using a comprehensive behavioral test battery. Molecular brain 31 30359304
2019 Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins. Scientific reports 26 31727973
2012 Complex formation of EphB1/Nck/Caskin1 leads to tyrosine phosphorylation and structural changes of the Caskin1 SH3 domain. Cell communication and signaling : CCS 19 23181695
2021 Silencing LINC00294 Restores Mitochondrial Function and Inhibits Apoptosis of Glioma Cells under Hypoxia via the miR-21-5p/CASKIN1/cAMP Axis. Oxidative medicine and cellular longevity 17 34777696
2016 A new mode of SAM domain mediated oligomerization observed in the CASKIN2 neuronal scaffolding protein. Cell communication and signaling : CCS 16 27549312
2017 miR-21a-5p Contributes to Porcine Hemagglutinating Encephalomyelitis Virus Proliferation via Targeting CASK-Interactive Protein1 In vivo and vitro. Frontiers in microbiology 13 28298907
2014 Differential synaptic distribution of the scaffold proteins Cask and Caskin1 in the bovine retina. Molecular and cellular neurosciences 12 25123431
2007 Gross genomic rearrangement involving the TSC2-PKD1 contiguous deletion syndrome: characterization of the deletion event by quantitative polymerase chain reaction deletion assay. American journal of kidney diseases : the official journal of the National Kidney Foundation 12 17185137
2023 Calcium/calmodulin-dependent serine protein kinase exacerbates mitochondrial calcium uniporter-related mitochondrial calcium overload by phosphorylating α-synuclein in Parkinson's disease. The international journal of biochemistry & cell biology 11 36754160
2017 The SH3 domain of Caskin1 binds to lysophosphatidic acid suggesting a direct role for the lipid in intracellular signaling. Cellular signalling 8 28104445
2025 Exploring Male-Specific Synaptic Plasticity in Major Depressive Disorder: A Single-Nucleus Transcriptomic Analysis Using Bioinformatics Methods. International journal of molecular sciences 3 40243907
2024 Molecular diagnostic yield of whole-exome sequencing in Saudi autistic children with epilepsy. International journal of health sciences 3 38721139
2023 A Missense Variant in CASKIN1's Proline-Rich Region Segregates with Psychosis in a Three-Generation Family. Genes 3 36672919
2022 Identification of Common Hub Genes in Human Dermal Fibroblasts Stimulated by Mechanical Stretch at Both the Early and Late Stages. Frontiers in surgery 3 35510126
2021 Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding. Cells 3 33467043
2025 Beyond the Genotype: A Multi-Omic Analysis of APOEe4's Role in Alzheimer's Disease. bioRxiv : the preprint server for biology 2 41279801
2025 CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses. Proceedings of the National Academy of Sciences of the United States of America 1 41223222
2024 SASH1 is a novel binding partner to disassemble Caskin1 tandem SAM homopolymer through heterogeneous SAM-SAM interaction. The FEBS journal 1 39688081

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