Affinage

OBSL1

Obscurin-like protein 1 · UniProt O75147

Length
1896 aa
Mass
206.9 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 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

OBSL1 is a cytoskeletal adaptor protein, closely related to obscurin, that functions as a scaffold linking growth-regulatory ubiquitin ligase activity to organelle and cytoskeletal organization (PMID:17289344, PMID:21572988). It localizes to the nuclear envelope and is required to maintain CUL7 protein levels, placing OBSL1 in a shared molecular pathway with CUL7 (PMID:19481195). OBSL1 physically binds CUL7 and recruits it to the Golgi apparatus, acting upstream of the CUL7(Fbxw8) ubiquitin ligase to drive Golgi morphogenesis, secretory trafficking, and dendrite elaboration in neurons (PMID:21572988); it additionally associates with CCDC8 in this growth-control pathway, though CCDC8 binds OBSL1 rather than CUL7 directly (PMID:21737058). Consistent with a growth-regulatory role, OBSL1-null fibroblasts show reduced GH-induced STAT5b/MAPK activation and blunted IGF1-induced AKT signaling (PMID:23018678). In striated muscle, OBSL1 acts redundantly with obscurin: single-gene loss is benign, but combined deletion impairs sarcolemmal stability and sarcoplasmic reticulum organization, while global OBSL1 knockout is embryonically lethal (PMID:31098411). In the heart, OBSL1 and obscurin together govern sarcoplasmic reticulum structure, calcium cycling, and mitochondrial architecture, with OBSL1 binding Atg4 proteins and dual loss producing abnormal mitophagy, elevated unfolded protein response, and diastolic dysfunction (PMID:40066567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 Medium

    Established the existence and tissue distribution of OBSL1 as an obscurin-related adaptor, defining its candidate subcellular niches before any function was known.

    Evidence Molecular cloning, splice-isoform characterization, and immunofluorescence in adult rat cardiac myocytes

    PMID:17289344

    Open questions at the time
    • No functional consequence demonstrated
    • Binding partners and pathway not yet defined
  2. 2009 Medium

    Linked OBSL1 to CUL7 by showing OBSL1 loss reduces CUL7 protein levels, establishing the two proteins act in a common pathway and OBSL1 stabilizes CUL7.

    Evidence SNP mapping, mutation identification, and localization/protein-level analysis in patient-derived cells

    PMID:19481195

    Open questions at the time
    • Mechanism of CUL7 stabilization not resolved
    • Direct OBSL1–CUL7 binding not yet shown in this study
  3. 2011 High

    Resolved how OBSL1 acts on CUL7 — direct complex formation that recruits CUL7 to the Golgi and drives Golgi morphogenesis and dendrite growth — defining OBSL1 as an upstream scaffold for the CUL7(Fbxw8) ligase.

    Evidence Reciprocal IP/MS, co-IP, and RNAi knockdown with morphological/functional readouts in primary neurons and rat cerebellum

    PMID:21572988

    Open questions at the time
    • Ubiquitination substrates downstream of the Golgi-localized complex not identified
    • How OBSL1 itself is targeted to the Golgi unresolved
  4. 2011 Medium

    Extended the growth-control module by showing CCDC8 binds OBSL1 (but not CUL7), defining the topology of the OBSL1–CUL7–CCDC8 pathway.

    Evidence Coimmunoprecipitation plus transcriptional co-association data

    PMID:21737058

    Open questions at the time
    • Single Co-IP without reciprocal validation or in vitro reconstitution
    • Functional output of the OBSL1–CCDC8 interaction not defined
  5. 2012 Medium

    Connected OBSL1 to growth-factor signaling by showing OBSL1-null cells have blunted GH and IGF1 responses, providing a cellular signaling basis for the growth phenotype.

    Evidence Phosphorylation assays for STAT5b/MAPK/AKT in patient-derived OBSL1-null fibroblasts after GH or IGF1 stimulation

    PMID:23018678

    Open questions at the time
    • Molecular mechanism by which OBSL1 engages GH/IGF1 receptor signaling unknown
    • Link to CUL7 ligase activity in this context not established
  6. 2019 High

    Defined OBSL1's role in striated muscle through genetic epistasis with obscurin, revealing functional redundancy for sarcolemmal and SR integrity and establishing the gene as essential for development.

    Evidence Conditional and global knockout mice, muscle proteomics, histology, and ultrastructure

    PMID:31098411

    Open questions at the time
    • Molecular basis of redundancy with obscurin unresolved
    • Cause of embryonic lethality of global knockout not pinpointed
  7. 2025 High

    Extended the muscle role to cardiac mitochondrial quality control, identifying Atg4 as a novel OBSL1 interactor and linking combined OBSL1/obscurin loss to defective mitophagy and diastolic dysfunction.

    Evidence Cardiac-specific double-knockout mice, fractionation, co-IP, EM, calcium imaging, metabolic assays, echocardiography

    PMID:40066567

    Open questions at the time
    • Whether OBSL1–Atg4 binding is direct and functionally required for mitophagy not dissected
    • Relationship between cardiac mitophagy role and the CUL7 ubiquitin-ligase pathway unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how OBSL1's distinct roles — CUL7-scaffolded ubiquitination, GH/IGF1 signaling, and obscurin-redundant muscle/mitophagy functions — are mechanistically unified or whether they share common substrates.
  • No structural model of OBSL1 in any complex
  • No identified ubiquitination substrate downstream of OBSL1–CUL7
  • Mechanism connecting growth signaling and cytoskeletal/organelle roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005635 nuclear envelope 1 GO:0005794 Golgi apparatus 1 GO:0005856 cytoskeleton 1
Pathway
GO:0140096 catalytic activity, acting on a protein 2
Partners
ATG4CCDC8CUL7OBSCN
Complex memberships
CUL7(Fbxw8) E3 ubiquitin ligase complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 CCDC8 physically interacts with OBSL1 (but not CUL7) as shown by coimmunoprecipitation, placing CCDC8 in the same pathway as CUL7 and OBSL1 in the control of mammalian growth. Coimmunoprecipitation American journal of human genetics Medium 21737058
2011 OBSL1 forms a physical complex with the scaffold protein CUL7, and this interaction localizes CUL7 to the Golgi apparatus. OBSL1 is required for Golgi morphogenesis and dendrite elaboration in neurons, acting upstream of the CUL7(Fbxw8) ubiquitin ligase. Loss of OBSL1 impairs Golgi complex morphology and secretory trafficking, and reduces dendrite growth without affecting axons. Immunoprecipitation/mass spectrometry, co-immunoprecipitation, RNAi knockdown with morphological and functional readouts in primary neurons and in vivo rat cerebellum PLoS biology High 21572988
2009 OBSL1 is a cytoskeletal adaptor protein that localizes to the nuclear envelope, and loss of OBSL1 leads to downregulation of CUL7 protein levels, implying a role for OBSL1 in the maintenance of CUL7 and that both proteins act in the same molecular pathway. High-density genome-wide SNP mapping, mutation identification, subcellular localization (nuclear envelope), and protein level analysis in patient-derived cells American journal of human genetics Medium 19481195
2007 OBSL1 is a cytoskeletal adaptor protein closely related to obscurin, expressed in multiple tissues, and localizes to intercalated discs, the perinuclear region, and overlying the Z lines and M bands of adult rat cardiac myocytes. Cloning, alternative splicing characterization, immunofluorescence localization in adult rat cardiac myocytes Genomics Medium 17289344
2012 In OBSL1-null fibroblasts, activation of STAT5b and MAPK in response to GH is reduced compared to controls, and activation of AKT in response to IGF1 is reduced at 5 min post-stimulation, indicating that OBSL1 is required for normal GH and IGF1 signaling. Signaling assays (phosphorylation of STAT5b, MAPK, AKT) in patient-derived OBSL1-null fibroblast cell lines following GH or IGF1 stimulation Journal of molecular endocrinology Medium 23018678
2019 Skeletal muscle-specific Obsl1 knockout mice have a benign phenotype similar to obscurin knockouts, but combined deletion of both Obsl1 and obscurin reveals functionally redundant roles for sarcolemmal stability and sarcoplasmic reticulum organization in skeletal muscle. Global Obsl1 knockout is embryonically lethal. Conditional and global knockout mouse models, mass spectrometry-based proteomics of muscle tissue, histological and ultrastructural analysis Communications biology High 31098411
2025 In cardiac muscle, Obsl1 (together with obscurin) plays roles in sarcoplasmic reticulum structure, calcium cycling, mitochondrial architecture and function. Obsl1 interacts with Atg4 proteins (novel interactors identified), and combined loss of obscurin and Obsl1 results in abnormal mitophagy, increased unfolded protein response, decreased Chchd3 (a MICOS complex protein) levels, and diastolic dysfunction. Cardiac-specific double-knockout mouse models, biochemical fractionation, co-immunoprecipitation (Atg4 as novel OBSL1 interactors), electron microscopy, calcium imaging, metabolic assays, echocardiography Circulation. Heart failure High 40066567

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. American journal of human genetics 95 21737058
2011 An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning. PLoS biology 86 21572988
2009 The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. American journal of human genetics 84 19481195
2007 Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to obscurin. Genomics 73 17289344
2012 Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. Journal of molecular endocrinology 50 23018678
2019 Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism. Communications biology 27 31098411
2016 A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene. Journal of clinical research in pediatric endocrinology 17 27796265
2013 Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation. Journal of pediatric endocrinology & metabolism : JPEM 14 23457316
2015 Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome. BMC genomics 8 25923536
2025 Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy. Circulation. Heart failure 5 40066567
2023 Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias. The Yale journal of biology and medicine 3 37780995
2024 Novel OBSL1 Variant in a Chinese Patient with 3M Syndrome: The c.458dupG Mutation May Be a Potential Hotspot Mutation in the Chinese Population. Journal of clinical research in pediatric endocrinology 2 38407006

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