MYZAP

MYZAP (Myozap) is an intercalated disc and adherens junction scaffold protein that couples cardiac and vascular cell-cell junctions to RhoA-dependent SRF transcriptional signaling (PMID:20093627, PMID:24698889). At the cardiomyocyte intercalated disc and in vascular endothelial adherens junction plaques, MYZAP directly binds desmoplakin and ZO-1 and assembles into a stable complex with junctional partners including N-cadherin, desmoglein-2, plakophilin-2, plakoglobin, and plectin (PMID:20093627, PMID:21992629). Through its ERM-like domain, MYZAP activates SRF-dependent transcription in a RhoA-dependent manner (PMID:20093627, PMID:24698889). MYZAP is required for normal contractile function, as ortholog knockdown produces cardiomyopathy in zebrafish (PMID:20093627) and biallelic loss-of-function variants cause severe human dilated cardiomyopathy with reduced contractile force in patient-derived iPSC-cardiomyocytes (PMID:35840178). Loss of MYZAP under pressure overload accelerates cardiac hypertrophy with dysregulated β-catenin/GSK-3β signaling, suppressed MAPK and MKL1/SRF activity, and disorganized intercalated disc proteins, while cardiac overexpression drives hypertrophy, LV dilation, MYZAP/desmoplakin protein aggregates, autophagy induction, unfolded-protein-response dysregulation, and apoptosis (PMID:24698889, PMID:26719331). MYZAP mRNA stability is post-transcriptionally controlled by the m6A reader YTHDF2 (PMID:37791304).

1. 2010 Medium

   Established MYZAP as an intercalated disc junctional scaffold by identifying its direct binding to desmoplakin and ZO-1, defining its physical place in the junctional architecture.

   Evidence Yeast 2-hybrid screen, direct binding assays, and immunolocalization in cardiomyocytes

   PMID:20093627

   Open questions at the time

   • Binding interfaces/domains not mapped
   • Stoichiometry of the junctional complex undefined
2. 2010 Low

   Linked MYZAP to Rho regulation through interaction with the negative Rho regulator MRIP, hinting at a junction-to-signaling connection.

   Evidence Single yeast 2-hybrid screen

   PMID:20093627

   Open questions at the time

   • Not validated by orthogonal methods
   • Functional consequence of MRIP binding not established
3. 2010 Medium

   Demonstrated that MYZAP transduces a transcriptional signal by activating SRF via its ERM-like domain in a RhoA-dependent manner, connecting junctional scaffolding to gene expression.

   Evidence Transcriptional reporter assays with domain mutants and Rho pathway inhibition, later corroborated in an overexpression mouse model

   PMID:20093627 PMID:24698889

   Open questions at the time

   • Direct biochemical link between MYZAP and RhoA activation not resolved
   • How junctional localization gates SRF activity unknown
4. 2010 Medium

   Showed MYZAP is required for cardiac contractile function in vivo, moving it from a binding partner to a functionally essential protein.

   Evidence Morpholino knockdown of the zebrafish ortholog with cardiac function readout

   PMID:20093627

   Open questions at the time

   • Morpholino specificity/off-target concerns
   • Mechanism linking loss to contractile failure not dissected
5. 2012 Medium

   Extended MYZAP beyond the heart by identifying it as a major cytoplasmic plaque component of vascular endothelial adherens junctions in a defined multiprotein complex.

   Evidence Immunoprecipitation, light and electron microscopy, and biochemical fractionation in vascular endothelia

   PMID:21992629

   Open questions at the time

   • Direct vs indirect nature of each co-precipitating partner not separated
   • Endothelial functional role not tested
6. 2014 High

   Defined the consequences of MYZAP excess, showing overexpression is itself pathogenic via SRF-driven hypertrophy, proteotoxic aggregation, autophagy, UPR dysregulation, and apoptosis.

   Evidence Cardiac-restricted transgenic mouse with histology, electron microscopy, and molecular pathway analysis

   PMID:24698889

   Open questions at the time

   • Whether aggregation or SRF activation is the primary driver of disease unclear
   • Dose-response threshold for pathology undefined
7. 2015 High

   Dissected MYZAP loss-of-function signaling, establishing it as a regulator balancing β-catenin/GSK-3β, MAPK, and MKL1/SRF pathways and maintaining intercalated disc organization under biomechanical stress.

   Evidence Knockout mice with transverse aortic constriction, Western blotting, and immunohistochemistry

   PMID:26719331

   Open questions at the time

   • Direct effectors downstream of MYZAP in each branch not identified
   • Order/causality among the dysregulated pathways unresolved
8. 2022 Medium

   Confirmed human disease relevance, showing biallelic loss-of-function MYZAP variants cause severe dilated cardiomyopathy with measurable contractile defects in patient cardiomyocytes.

   Evidence Exome sequencing plus iPSC-derived cardiomyocyte contractility assays and tissue analysis from a patient family

   PMID:35840178

   Open questions at the time

   • Single family limits genetic generalizability
   • Molecular step from MYZAP loss to impaired contraction not pinpointed
9. 2023 Medium

   Identified post-transcriptional control of MYZAP, showing the m6A reader YTHDF2 binds Myzap mRNA and governs its stability with cardiac consequences.

   Evidence Cardiomyocyte-specific YTHDF2 knockout mice, RNA immunoprecipitation, mRNA stability assays, and proteomics

   PMID:37791304

   Open questions at the time

   • m6A site(s) on Myzap mRNA not mapped
   • Whether YTHDF2 effect on remodeling is solely MYZAP-mediated unclear
10. 2020 Low

    Implicated a protein-stability partner, with Dysbindin interaction and Dtnbp1 loss reducing cardiac MYZAP levels.

    Evidence Sandy (Dtnbp1 KO) mice with Western blotting and prior interaction data

    PMID:33142804

    Open questions at the time

    • Direct Dysbindin–MYZAP binding not confirmed by orthogonal method
    • Mechanism of stabilization unknown
11. 2024 Low

    Placed MYZAP upstream of conduction-related proteins, with overexpression raising PKP2 and Nav1.5 and reducing atrial fibrillation.

    Evidence Transgenic and AAV MYZAP overexpression mice with AF incidence and Western blotting

    PMID:39507261

    Open questions at the time

    • Biochemical link between MYZAP and PKP2/Nav1.5 not dissected
    • Inference from overexpression only

• How MYZAP mechanically and biochemically couples junctional binding to selective activation of RhoA/SRF versus suppression of β-catenin/MAPK branches, and the direct effectors mediating contractile output, remain unresolved.
• No structural model of MYZAP or its complexes
• Direct enzymatic/effector partners controlling RhoA undefined
• Mechanism translating junctional scaffolding to contractile force unknown