Affinage

MYZAP

Myocardial zonula adherens protein · UniProt P0CAP1

Length
466 aa
Mass
54.2 kDa
Annotated
2026-04-29
27 papers in source corpus 8 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYZAP (Myozap) is an intercalated disc scaffolding protein essential for cardiac structure and contractile function. It directly binds desmoplakin, ZO-1, N-cadherin, plakophilin-2, plakoglobin, and plectin at adherens junction plaques, and activates RhoA-dependent SRF transcription through its ERM-like domain, linking cell–cell junctions to hypertrophic gene regulation (PMID:20093627, PMID:21992629, PMID:26719331). MYZAP protein levels are regulated post-transcriptionally by YTHDF2-mediated decay of m6A-modified MYZAP mRNA, and upstream by dysbindin-dependent stabilization; both loss and overexpression of MYZAP cause cardiomyopathy in mice through dysregulated RhoA/SRF, β-catenin/GSK-3β, and intercalated disc disorganization (PMID:24698889, PMID:26719331, PMID:37791304, PMID:33142804). Biallelic loss-of-function variants in MYZAP cause severe dilated cardiomyopathy in humans, confirmed by impaired contractile force in patient-derived iPSC-cardiomyocytes (PMID:35840178).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2010 High

    The identity of MYZAP as an intercalated disc protein that bridges junctional scaffolding to transcriptional signaling was established, answering how the cardiac intercalated disc communicates with nuclear gene programs.

    Evidence Yeast two-hybrid, co-IP, immunolocalization, transcriptional reporter assays, domain mutagenesis, and zebrafish morpholino knockdown in a single foundational study

    PMID:20093627

    Open questions at the time
    • Mammalian in vivo loss-of-function model not yet available
    • Structural basis of ERM-like domain activation of RhoA unknown
    • Endogenous MRIP–MYZAP stoichiometry and regulation not defined
  2. 2012 High

    MYZAP was shown to be a bona fide adherens junction plaque component with a broad interactome including N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin, extending its role beyond a simple desmoplakin-binding protein.

    Evidence Reciprocal immunoprecipitation with new specific antibodies, immunolocalization by light and electron microscopy in vascular endothelial cells

    PMID:21992629

    Open questions at the time
    • Direct versus indirect binding not resolved for all partners
    • Functional consequence of individual interactions not tested
    • Endothelial-specific functions of MYZAP remain unexplored
  3. 2014 High

    Gain-of-function demonstrated that excess MYZAP is sufficient to cause cardiomyopathy through SRF-dependent hypertrophic gene activation, protein aggregate formation, and induction of autophagy and apoptosis, establishing dose sensitivity.

    Evidence Cardiac-specific Myozap transgenic mice with pressure overload, ultrastructural and molecular pathway analysis

    PMID:24698889

    Open questions at the time
    • Mechanism of aggregate nucleation (MYZAP–desmoplakin) not resolved
    • Relative contribution of autophagy versus apoptosis to pathology unknown
    • Whether aggregate toxicity is separable from SRF transcriptional activation not tested
  4. 2015 High

    Mammalian loss-of-function revealed that MYZAP is required to maintain intercalated disc integrity and suppress β-catenin/GSK-3β signaling under stress, with its absence causing accelerated heart failure and intercalated disc disorganization.

    Evidence Myozap knockout mice subjected to transverse aortic constriction, western blotting, pathway analysis

    PMID:26719331

    Open questions at the time
    • Direct mechanism linking MYZAP loss to β-catenin activation not defined
    • Cell-type-specific versus global contributions not dissected
    • Whether MKL1/SRF inhibition is a cause or consequence of remodeling is unclear
  5. 2020 Medium

    Dysbindin was identified as an upstream stabilizer of MYZAP protein that co-activates the MYZAP–RhoA–SRF axis, connecting schizophrenia-related biology to cardiac hypertrophy signaling.

    Evidence Protein interaction studies and sandy (dysbindin-null) mouse hearts with western blotting

    PMID:33142804

    Open questions at the time
    • Mechanism by which dysbindin stabilizes MYZAP protein not established
    • Whether dysbindin–MYZAP interaction is direct or scaffolded is unresolved
    • In vivo rescue experiment not performed
  6. 2022 High

    Human genetic validation established MYZAP as a dilated cardiomyopathy gene, with biallelic truncating variants causing disease and iPSC-cardiomyocytes confirming a cell-autonomous contractile defect.

    Evidence Exome sequencing of affected individual, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy

    PMID:35840178

    Open questions at the time
    • Only a single family reported; additional kindreds needed to confirm penetrance
    • Molecular mechanism downstream of truncation (loss of specific domains/interactions) not dissected
    • No rescue experiment with wild-type MYZAP in patient iPSC-CMs
  7. 2023 High

    YTHDF2-mediated m6A-dependent mRNA decay was identified as a key post-transcriptional mechanism controlling MYZAP abundance, explaining how epitranscriptomic dysregulation can phenocopy MYZAP overexpression cardiomyopathy.

    Evidence Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation

    PMID:37791304

    Open questions at the time
    • Specific m6A sites on MYZAP mRNA not mapped
    • Whether METTL3-mediated writing is dynamically regulated in cardiac stress is unknown
    • Rescue by MYZAP knockdown in YTHDF2-KO hearts not shown
  8. 2024 Medium

    MYZAP was placed upstream of a PKP2–Nav1.5 axis that modulates atrial conduction velocity and atrial fibrillation susceptibility, expanding its role from structural scaffolding to electrical remodeling.

    Evidence AAV9-mediated overexpression and cardiac-specific transgenic mice, electrophysiological measurements, western blotting

    PMID:39507261

    Open questions at the time
    • Direct physical interaction between MYZAP and PKP2 not biochemically confirmed
    • Loss-of-function atrial phenotype not examined
    • Anti-inflammatory mechanism (TLR2/TLR4 downregulation) is correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of MYZAP's ERM-like domain activation of RhoA, the stoichiometry of MYZAP within the intercalated disc macromolecular complex, and whether MYZAP has functions beyond the heart remain open questions.
  • No crystal or cryo-EM structure available
  • Quantitative model of MYZAP's junctional stoichiometry lacking
  • Non-cardiac phenotypes (endothelial, epithelial) not systematically explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 3
Partners
CDH2DSPDTNBP1JUPMRIPPKP2PLECTJP1
Complex memberships
Intercalated disc adherens junction complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Myozap localizes to the intercalated disc (ID) of cardiomyocytes and directly binds desmoplakin and zonula occludens-1 (ZO-1); it also interacts with myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity, identified by yeast two-hybrid screen. Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization Circulation research High 20093627
2010 Myozap activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a RhoA-dependent manner, linking the intercalated disc to cardiac gene regulation. Transcriptional reporter assays, domain mutagenesis, in vivo zebrafish knockdown Circulation research High 20093627
2010 In vivo knockdown of the Myozap ortholog in zebrafish leads to severe contractile dysfunction and cardiomyopathy, establishing a required role for Myozap in cardiac function. Morpholino-based knockdown in zebrafish with cardiac phenotype assessment Circulation research High 20093627
2012 Myozap is a component of adherens junction plaques in vascular endothelial cells and forms stable complexes with N-cadherin, desmoplakin, desmoglein-2, plakophilin-2, plakoglobin, and plectin as demonstrated by rigorous immunoprecipitation. Immunoprecipitation, immunolocalization (light and electron microscopy) Journal of cellular and molecular medicine High 21992629
2014 Cardiac overexpression of Myozap in transgenic mice induces cardiomyopathy with hypertrophy and LV dilation, upregulation of SRF-dependent hypertrophic gene expression, formation of protein aggregates containing Myozap and desmoplakin, induction of autophagy, dysregulation of the unfolded protein response, and apoptosis. Transgenic mouse model, pressure overload (TAC), ultrastructural analysis, molecular pathway analysis Journal of molecular and cellular cardiology High 24698889
2015 Myozap-null (Mzp-/-) mice under pressure overload show accelerated cardiac hypertrophy, severe contractile dysfunction, and increased mortality; molecularly, loss of Myozap leads to activation of β-catenin/GSK-3β signaling and inhibition of MAPK and MKL1/SRF pathways, with disorganization of intercalated disc proteins (N-cadherin, desmoplakin, connexin-43, ZO-1). Myozap knockout mouse model, transverse aortic constriction, western blotting, pathway analysis The Journal of biological chemistry High 26719331
2020 Dysbindin interacts with Myozap and activates Myozap-RhoA-mediated SRF signaling to promote cardiomyocyte hypertrophy in vitro; loss of Dysbindin in sandy mice dramatically reduces Myozap protein levels in the heart. Protein interaction studies, dysbindin knockout mouse (sandy mice), western blotting Cells Medium 33142804
2023 YTHDF2, an m6A mRNA-binding protein, binds m6A-modified Myzap mRNA and controls its stability; loss of YTHDF2 in cardiomyocytes increases MYZAP protein levels and causes cardiac dysfunction, placing MYZAP as a key downstream target of post-transcriptional m6A regulation. Cardiomyocyte-specific YTHDF2 knockout mouse, proteomics, RNA-binding protein immunoprecipitation JACC. Basic to translational science High 37791304
2022 Biallelic loss-of-function (homozygous truncating) variant in MYZAP causes severe dilated cardiomyopathy; patient-derived iPSC-cardiomyocytes show significantly lower contractile force and prolonged contraction/relaxation, confirming MYZAP is required for normal cardiomyocyte contractile function. Exome sequencing, patient iPSC-cardiomyocyte functional assay, immunohistochemistry, western blot, electron microscopy Cold Spring Harbor molecular case studies High 35840178
2024 MYZAP overexpression in atrial tissue following myocardial infarction increases PKP2 and Nav1.5 levels; MYZAP engages a MYZAP-PKP2-Nav1.5 signaling pathway that modulates atrial conduction velocity and AF incidence, while also downregulating TLR2, TLR4, and inflammation-related factors. Cardiac-specific transgenic CCRR overexpression mice, AAV9-mediated overexpression, electrophysiological measurements, western blotting iScience Medium 39507261

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 GUP1 of Saccharomyces cerevisiae encodes an O-acyltransferase involved in remodeling of the GPI anchor. Molecular biology of the cell 116 16597698
2000 GUP1 and its close homologue GUP2, encoding multimembrane-spanning proteins involved in active glycerol uptake in Saccharomyces cerevisiae. Molecular microbiology 74 10931309
2010 Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo. Circulation research 52 20093627
2018 Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Communications biology 43 30271950
2007 Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol uptake/transporter 1, acts as a negative regulator for N-terminal palmitoylation of Sonic hedgehog. The FEBS journal 33 18081866
2014 Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy. Journal of molecular and cellular cardiology 27 24698889
2015 Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase/Serum-response Factor and β-Catenin/GSK-3β Protein Signaling. The Journal of biological chemistry 25 26719331
2012 The plaque protein myozap identified as a novel major component of adhering junctions in endothelia of the blood and the lymph vascular systems. Journal of cellular and molecular medicine 23 21992629
2012 Programmed cell death in Saccharomyces cerevisiae is hampered by the deletion of GUP1 gene. BMC microbiology 21 22617017
2005 Subcellular localization and functional expression of the glycerol uptake protein 1 (GUP1) of Saccharomyces cerevisiae tagged with green fluorescent protein. The Biochemical journal 19 15813700
2007 The Gup1 homologue of Trypanosoma brucei is a GPI glycosylphosphatidylinositol remodelase. Molecular microbiology 18 18036137
2023 Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling. JACC. Basic to translational science 16 37791304
2004 Expression studies of GUP1 and GUP2, genes involved in glycerol active transport in Saccharomyces cerevisiae, using semi-quantitative RT-PCR. Current genetics 15 15278288
2011 Protein myozap--a late addition to the molecular ensembles of various kinds of adherens junctions. Cell and tissue research 13 22160502
2010 Over-expression of functional Saccharomyces cerevisiae GUP1, induces proliferation of intracellular membranes containing ER and Golgi resident proteins. Biochimica et biophysica acta 12 21167129
2021 GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy. Frontiers in genetics 9 34899865
2018 Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage. Clinical and experimental dermatology 8 29768670
2016 Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications. Journal of developmental biology 7 29615596
2018 The human GCOM1 complex gene interacts with the NMDA receptor and internexin-alpha. Gene 6 29339073
2017 Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America. International journal of dermatology 6 29152726
2017 PER1, GUP1 and CWH43 of methylotrophic yeast Ogataea minuta are involved in cell wall integrity. Yeast (Chichester, England) 5 29027702
2017 Patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with MYZAP, p0071, desmoplakins 1 and 2 and ARVCF. Clinical and experimental dermatology 5 29034528
2022 A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy. Cold Spring Harbor molecular case studies 4 35840178
2018 Saccharomyces cerevisiae mitochondrial Por1/yVDAC1 (voltage-dependent anion channel 1) interacts physically with the MBOAT O-acyltransferase Gup1/HHATL in the control of cell wall integrity and programmed cell death. FEMS yeast research 4 30184078
2024 CCRR regulate MYZAP-PKP2-Nav1.5 signaling pathway in atrial fibrillation following myocardial infarction. iScience 2 39507261
2020 Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice. Cells 2 33142804
2021 Physical, genetic and functional interactions between the eisosome protein Pil1 and the MBOAT O-acyltransferase Gup1. FEMS yeast research 1 33355361