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Showing CHP1 — CHP is a alias.

CHP1

Calcineurin B homologous protein 1 · UniProt Q99653

Length
195 aa
Mass
22.5 kDa
Annotated
2026-06-09
31 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHP1 (calcineurin B homologous protein 1) is an N-myristoylated EF-hand Ca2+-binding protein that acts as an obligate regulatory subunit and chaperone for membrane transporters and a multifunctional intracellular scaffold (PMID:34108458, PMID:30846317). Its best-defined role is as an obligate binding partner of the sodium/proton exchangers NHE1 and NHE3, where it promotes biosynthetic maturation (glycosylation), cell-surface expression, and pH-sensitivity; cryo-EM of both complexes shows CHP1 differentially engaging the inward- and outward-facing elevator states of the transporter dimer to confer pH regulation (PMID:34108458, PMID:35613257). Loss of correct CHP1-dependent NHE1 maturation underlies disease: truncating EF-hand mutants and the aggregation-prone p.K19del allele reduce soluble CHP1 and NHE1 membrane targeting, causing cerebellar ataxia and Purkinje cell axon degeneration, with wild-type human CHP1 rescuing Chp1-deficient zebrafish phenotypes (PMID:23904602, PMID:29379881). In parallel, CHP1 binds and activates the rate-limiting ER glycerolipid-synthesis enzymes GPAT4 and GPAT3, an interaction dependent on CHP1 N-myristoylation and required for GPAT stability, activity, and lipid-droplet localization, thereby controlling fatty acid incorporation and triacylglycerol storage (PMID:30846317, PMID:40875810). Beyond transport and lipid metabolism, CHP1 functions as a calcium-dependent scaffold and calcineurin inhibitor: it interacts with PLS3 and restrains calcineurin to control dynamin-1 dephosphorylation and macropinocytosis (PMID:29961886), and nuclear CHP1 binds the RNA polymerase I factor UBF in a Ca2+-inhibitable manner to attenuate rRNA synthesis (PMID:20720019).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2010 Medium

    Established that CHP1 is not solely a membrane-associated cofactor but shuttles between plasma membrane, Golgi, and nucleus, linking its localization to a transcriptional function previously unrecognized for this Ca2+-binding protein.

    Evidence Subcellular fractionation, co-precipitation screen, nuclear export motif mutagenesis, and rRNA synthesis assay in fibroblasts

    PMID:20720019

    Open questions at the time
    • Mechanism of Ca2+-regulated nucleocytoplasmic shuttling not structurally defined
    • Direct effect on Pol I transcription machinery beyond UBF abundance not resolved
  2. 2013 High

    Resolved how CHP1 functionally supports NHE1, showing it is required for full glycosylation/maturation and membrane delivery, and that EF-hand mutants phenocopy Nhe1 loss in causing Purkinje axon degeneration.

    Evidence Positional cloning, point mutagenesis, subcellular fractionation, and Nhe1-knockout genetic epistasis in mouse

    PMID:23904602

    Open questions at the time
    • Molecular basis of glycosylation defect not defined
    • Whether NHE1 alone accounts for the neurodegenerative phenotype unresolved
  3. 2018 High

    Defined a CHP1-calcineurin signaling axis, showing CHP1 inhibits calcineurin and interacts with PLS3, and that lowering CHP1 restores dynamin-1 dephosphorylation and macropinocytosis in SMN-depleted motor neurons.

    Evidence Yeast two-hybrid, reciprocal co-IP, pull-down, calcineurin phosphatase activity, phosphorylation, and macropinocytosis assays

    PMID:29961886

    Open questions at the time
    • Stoichiometry of CHP1-calcineurin inhibition not quantified
    • Functional role of PLS3 interaction not fully separated from calcineurin effect
  4. 2018 High

    Connected CHP1 to human disease, demonstrating the p.K19del mutant aggregates and fails to assemble into functional complexes, reducing NHE1 membrane targeting and causing cerebellar ataxia.

    Evidence Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, and zebrafish morpholino rescue with human CHP1 mRNA

    PMID:29379881

    Open questions at the time
    • How aggregation is triggered at the structural level unresolved
    • Contribution of non-NHE1 CHP1 functions to ataxia not assessed
  5. 2019 High

    Identified a metabolic function distinct from transport regulation, showing CHP1 binds and activates GPAT4 via an N-myristoylation-dependent interface to drive ER glycerolipid synthesis and lipid storage.

    Evidence CRISPR screens, lipidomics, binding/activity assays, and N-myristoylation mutagenesis in mammalian cells and invertebrates

    PMID:30846317

    Open questions at the time
    • Whether CHP1 Ca2+-binding modulates GPAT activation not tested
    • Structural basis of the GPAT4 interface not determined at this stage
  6. 2020 Medium

    Clarified the Ca2+-dependence of CHP1-NHE1 binding, showing CHP1 retains an accessible hydrophobic CBD-binding pocket even without Ca2+, distinguishing its regulation from the Ca2+-sensitive paralog CHP2.

    Evidence Fluorescent probe hydrophobicity assay and isothermal titration calorimetry on CHP1/CHP2 with the NHE1 CHP-binding domain

    PMID:31912575

    Open questions at the time
    • Physiological consequence of Ca2+-independent CBD binding in cells not shown
    • Does not address Ca2+ effects on full-length transporter regulation
  7. 2021 High

    Provided the structural mechanism of CHP1-mediated NHE1 regulation, showing NHE1 is a symmetrical dimer using elevator motions and that CHP1 differentially contacts the two conformational states to confer pH-sensitivity.

    Evidence Cryo-EM of human NHE1-CHP1 in inward-facing and inhibitor-bound outward-facing conformations

    PMID:34108458

    Open questions at the time
    • Dynamics of the conformational cycle in a membrane not directly observed
    • Role of CHP1 myristoylation in the structural context not resolved
  8. 2022 High

    Extended the structural model to NHE3, revealing an autoinhibitory helix-loop-helix element blocking the cavity and two phosphatidylinositol lipids stabilizing the CHP1-bound complex.

    Evidence Cryo-EM of the human NHE3-CHP1 complex in inward-facing conformation

    PMID:35613257

    Open questions at the time
    • Outward-facing NHE3-CHP1 state not captured
    • Functional role of bound phosphatidylinositol on transport rate not directly demonstrated
  9. 2025 High

    Broadened the lipid-synthesis role, showing CHP1 is required for both GPAT3 and GPAT4 stability, activity, and lipid-droplet targeting and helps route AGPAT3 and DGAT2 to droplets past seipin-mediated restriction.

    Evidence Mutational analyses, structural modeling, enzymatic activity assays, lipid-droplet imaging, and loss-of-function experiments

    PMID:40875810

    Open questions at the time
    • Direct structures of CHP1-GPAT complexes not solved
    • Mechanism of bypassing seipin restriction not defined
  10. 2025 Medium

    Implicated CHP1 as a phosphorylated scaffold in immune signaling, where CaMK4 phosphorylation drives Calhm6-CHP1-CaMK4 membrane localization to promote CREB1 activation and M2 macrophage polarization.

    Evidence Co-IP, phosphorylation assay, membrane fractionation, and macrophage polarization assays

    PMID:40999918

    Open questions at the time
    • CaMK4 phosphosite on CHP1 not mapped
    • Direct vs indirect role of CHP1 in CREB1 activation not separated
  11. 2026 Medium

    Linked CHP1 to mechanosensing and tumor biology through a CHP1-TMEM87A complex regulating YAP-GPC6-WNT5A/Hedgehog signaling and metastasis.

    Evidence Co-IP, CETSA, microscale thermophoresis, surface plasmon resonance, and in vivo orthotopic tumor model

    PMID:42258092

    Open questions at the time
    • Structural basis of CHP1-TMEM87A binding not resolved
    • How CHP1 transduces mechanical input to the signaling axis unclear
  12. 2026 Medium

    Identified CHP1 as a direct drug target, where Exendin-4 binding reduces CHP1 levels and modulates apoptosis and calcium homeostasis via the CHP1/NHE1 complex.

    Evidence Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression in in vitro and in vivo AMD models

    PMID:41679663

    Open questions at the time
    • Binding site of Exendin-4 on CHP1 not mapped
    • Mechanism by which binding lowers CHP1 protein levels not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHP1's distinct activities — transporter chaperoning, GPAT activation, calcineurin inhibition, and nuclear UBF binding — are coordinated by Ca2+ and myristoylation within a single cell remains unresolved.
  • No unified model integrating Ca2+ sensing across CHP1's multiple effector complexes
  • Whether competing partners share the same hydrophobic pocket is undefined
  • Tissue-specific dominance of each function not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1 GO:0005794 Golgi apparatus 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2
Partners
CAMK4GPAT3GPAT4NHE1NHE3PLS3TMEM87AUBF
Complex memberships
Calhm6-CHP1-CaMK4 complexNHE1-CHP1 complexNHE3-CHP1 complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 CHP1 is an obligate binding partner of NHE1 that promotes NHE1 biosynthetic maturation, cell surface expression, and pH-sensitivity. Cryo-EM structures of the human NHE1-CHP1 complex in inward-facing and inhibitor-bound outward-facing conformations show NHE1 assembles as a symmetrical homodimer undergoing elevator-like conformational changes; CHP1 differentially associates with the two conformational states of each NHE1 monomer, underlying regulation of pH-sensitivity. Cryo-EM structure determination of NHE1-CHP1 complex in two conformational states Nature communications High 34108458
2022 CHP1 binds NHE3 and facilitates its maturation, plasmalemmal expression, and pH sensitivity. Cryo-EM structure of the human NHE3-CHP1 complex in inward-facing conformation reveals a cytosolic helix-loop-helix autoinhibitory element that blocks the intracellular cavity, and two phosphatidylinositol molecules that bind juxtamembrane sides to stabilize the complex and may enhance transport activity. Cryo-EM structure determination of NHE3-CHP1 complex Science advances High 35613257
2019 CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis at the ER. CHP1 N-myristoylation is required for this activation, forming a key molecular interface between CHP1 and GPAT4. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. CRISPR-based genetic screens, unbiased lipidomics, binding and activity assays, N-myristoylation mutagenesis Molecular cell High 30846317
2025 CHP1 is a critical regulator of both GPAT3 and GPAT4, required for their stability, enzymatic activity, and lipid droplet localization. CHP1 also facilitates localization of downstream TAG synthesis enzymes AGPAT3 and DGAT2 to lipid droplets by circumventing seipin-mediated restriction. Hydrophobic interfaces mediating CHP1-GPAT interaction were identified by structural modeling and mutational analyses. Mutational analyses, structural modeling, enzymatic activity assays, lipid droplet imaging, loss-of-function experiments Proceedings of the National Academy of Sciences of the United States of America High 40875810
2013 CHP1 assists in the full glycosylation (biosynthetic maturation) of NHE1 required for membrane localization of this transporter. Truncated CHP1 isoforms with mutations in the EF-hand domain are defective in stimulating NHE1 biosynthetic maturation, resulting in reduced membrane localization of NHE1 at axon terminals and subsequent Purkinje cell axon degeneration. Genetic ablation of Nhe1 also causes Purkinje cell axon degeneration, confirming functional convergence. Positional cloning, point mutagenesis, subcellular fractionation, genetic epistasis (Nhe1 knockout) The Journal of neuroscience High 23904602
2018 Mutant CHP1 (p.K19del) fails to integrate into functional protein complexes and is prone to aggregation, leading to diminished soluble CHP1 and reduced membrane targeting of NHE1, causing cerebellar ataxia. Wild-type but not mutant human CHP1 mRNA rescued Chp1-deficient zebrafish movement defects and cerebellar hypoplasia. Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, zebrafish Morpholino rescue experiments Neurology. Genetics High 29379881
2018 CHP1 directly interacts with PLS3 (Plastin 3), confirmed by co-immunoprecipitation and pull-down assays. CHP1 acts as an inhibitor of calcineurin phosphatase; CHP1 reduction restores calcineurin activity, leading to dephosphorylation of dynamin 1 and restoration of macropinocytosis in Smn-depleted motor neuron cells. Yeast-two-hybrid screen, co-immunoprecipitation, pull-down assay, macropinocytosis assay, calcineurin phosphatase activity assay, phosphorylation analysis Brain High 29961886
2010 CHP1 localizes to the plasma membrane, Golgi, and nucleus in a regulated manner: predominantly nuclear in quiescent fibroblasts and translocated to cytoplasmic compartments upon growth stimulation. Nuclear CHP1 binds upstream binding factor (UBF), a component of the RNA polymerase I complex, in a Ca2+-inhibitable manner, and nuclear retention of CHP1 attenuates UBF nucleolar abundance and inhibits rRNA synthesis. Subcellular fractionation, co-precipitation/pulldown screen, nuclear export motif mutagenesis, rRNA synthesis assay The Journal of biological chemistry Medium 20720019
2020 Ca2+ induces conformational changes in CHP1 (detected by fluorescent probe hydrophobicity assay), but unlike CHP2, the CHP1 hydrophobic pocket that binds the NHE1 CHP-binding domain (CBD) remains accessible in the absence of Ca2+. Both CHP1 and CHP2 interact with CBD with nanomolar affinity (ITC), but Ca2+ depletion does not significantly affect CHP1:CBD affinity (whereas it reduces CHP2:CBD affinity 7-fold), indicating isoform-specific Ca2+-dependent regulation of NHE1 interaction. Fluorescent probe hydrophobicity (FPH) assay, isothermal titration calorimetry (ITC) FASEB journal Medium 31912575
2025 CHP1 serves as a scaffold protein that undergoes phosphorylation by CaMK4, which enhances localization of the Calhm6-CHP1-CaMK4 complex to the cell membrane, promoting Creb1 activation and M2-like macrophage polarization in a calcium-dependent manner. Co-immunoprecipitation, phosphorylation assay, membrane fractionation, macrophage polarization assays Advanced science Medium 40999918
2026 CHP1 interacts with transmembrane protein 87A (TMEM87A), forming a mechanosensing complex. CHP1 ablation disrupts spheroid morphogenesis and the CHP1-TMEM87A complex regulates metastasis via the YAP-GPC6-WNT5A/Hedgehog signaling axis. Disruption of CHP1-TMEM87A binding by sodium gluconate inhibits downstream Hedgehog/PTCH1 signaling. Co-immunoprecipitation, CETSA, microscale thermophoresis, surface plasmon resonance, in vivo orthotopic tumor model Molecular biomedicine Medium 42258092
2026 EX-4 (Exendin-4) binds CHP1 directly (identified by proteome microarray and pull-down LC-MS/MS), reducing CHP1 protein expression concentration-dependently. This interaction alleviates apoptosis and restores calcium homeostasis through the CHP1/NHE1 complex. CHP1 knockdown or overexpression reverses the inhibitory effects of EX-4 on apoptosis and calcium signaling. Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression, in vitro and in vivo AMD model Biochemical pharmacology Medium 41679663

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. The EMBO journal 179 15372076
2019 CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4. Molecular cell 85 30846317
2021 Structure and mechanism of the human NHE1-CHP1 complex. Nature communications 74 34108458
2005 RNA interference (RNAi)-dependent and RNAi-independent association of the Chp1 chromodomain protein with distinct heterochromatic loci in fission yeast. Molecular and cellular biology 70 15743828
2012 Intrinsic nucleic acid-binding activity of Chp1 chromodomain is required for heterochromatic gene silencing. Molecular cell 52 22727667
2018 CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis. Brain : a journal of neurology 46 29961886
1989 Analysis of the complete nucleotide sequence of Chp1, a phage which infects avian Chlamydia psittaci. The Journal of general virology 45 2607341
2008 Chp1-Tas3 interaction is required to recruit RITS to fission yeast centromeres and for maintenance of centromeric heterochromatin. Molecular and cellular biology 37 18212052
2011 The Chp1-Tas3 core is a multifunctional platform critical for gene silencing by RITS. Nature structural & molecular biology 32 22081013
2003 Chp-1 and melusin, two CHORD containing proteins in vertebrates. FEBS letters 31 12965203
1998 The fission yeast chromo domain encoding gene chp1(+) is required for chromosome segregation and shows a genetic interaction with alpha-tubulin. Nucleic acids research 31 9722643
2013 CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 23904602
2019 HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson's Disease and Dementia with Lewy Bodies. Journal of Parkinson's disease 22 30741686
2018 Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. Neurology. Genetics 20 29379881
2022 Structural basis of autoinhibition of the human NHE3-CHP1 complex. Science advances 17 35613257
2016 The Chp1 chromodomain binds the H3K9me tail and the nucleosome core to assemble heterochromatin. Cell discovery 17 27462451
2024 Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis. Nature communications 16 38360885
2010 Nuclear-localized calcineurin homologous protein CHP1 interacts with upstream binding factor and inhibits ribosomal RNA synthesis. The Journal of biological chemistry 12 20720019
2020 Azorhizobium caulinodans c-di-GMP phosphodiesterase Chp1 involved in motility, EPS production, and nodulation of the host plant. Applied microbiology and biotechnology 11 32002604
2016 The canine prostate cancer cell line CHP-1 shows over-expression of the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α. Veterinary and comparative oncology 10 26762899
2020 The C. elegans CHP1 homolog, pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen. PLoS pathogens 9 31917826
2022 Combinatorial ASO-mediated therapy with low dose SMN and the protective modifier Chp1 is not sufficient to ameliorate SMA pathology hallmarks. Neurobiology of disease 7 35724821
2019 PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice. Frontiers in neuroscience 6 31607845
2020 Calcium affects CHP1 and CHP2 conformation and their interaction with sodium/proton exchanger 1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 5 31912575
2020 The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and in human cells. eLife 5 32053105
2025 Calhm6 Governs Macrophage Polarization Through Chp1-Camk4-Creb1 Axis and Ectosomal Delivery in Inflammatory Responses. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40999918
2019 Nuclear aconitase antagonizes heterochromatic silencing by interfering with Chp1 binding to DNA. Biochemical and biophysical research communications 4 31255284
2025 CHP1 promotes lipid droplet growth and regulates the localization of key enzymes for triacylglycerol synthesis. Proceedings of the National Academy of Sciences of the United States of America 2 40875810
2025 Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses. Biomolecules 1 40723891
2026 Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex. Biochemical pharmacology 0 41679663
2026 Targeting the Calcineurin Homologous Protein 1 (CHP1)-Transmembrane Protein 87A (TMEM87A) mechanosensing complex: a druggable vulnerability in metastatic ovarian cancer. Molecular biomedicine 0 42258092

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