Affinage

MPP1

55 kDa erythrocyte membrane protein · UniProt Q00013

Length
466 aa
Mass
52.3 kDa
Annotated
2026-06-10
23 papers in source corpus 13 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MPP1/p55 is a palmitoylated MAGUK scaffolding protein that organizes the lateral order of plasma membrane raft nanodomains and couples this organization to receptor signaling and cell polarity (PMID:23507198, PMID:35159121). Its central biochemical activity is a direct, high-affinity interaction with flotillin-1 and flotillin-2 through a defined flotillin-binding motif in the D5 domain; this interaction is distinct from MPP1's protein 4.1-dependent contacts and is required to maintain erythrocyte membrane fluidity and order (PMID:28865798, PMID:34285255). Reconstitution of MPP1 with recombinant flotillins in synthetic vesicles is sufficient to drive coexistence of liquid-ordered and liquid-disordered domains, establishing the MPP1-flotillin assembly as a minimal unit capable of remodeling membrane lateral organization (PMID:41061789). Mechanistically, MPP1 captures and temporally immobilizes flotillin-based nanoclusters and confines raft lipids such as sphingomyelin and Thy-1 (PMID:35159121), and its palmitoylation — written by DHHC17 in red blood cells — is required for detergent-resistant membrane formation and membrane order (PMID:22496366, PMID:23507198). This raft-organizing function underlies MPP1's control of multiple raft-dependent signaling outputs: spatial restriction of PIP3 and downstream Akt activation that drives neutrophil chemotactic polarity (PMID:19897731), H-Ras GDP/GTP exchange and H-Ras-Raf coupling in insulin receptor signaling (PMID:29719614, PMID:34285255), and RTK/MAP-kinase signaling in erythroid cells (PMID:23507198). MPP1 additionally functions as a scaffold linking polarity and cytoskeletal networks through directional heterodimerization with MPP5/Pals1 and interaction with whirlin at the retinal outer limiting membrane (PMID:17584769) and through nanomolar-affinity binding to the FERM domain of NF2/merlin (PMID:19144871). Roles in cardiac AGTR1 regulation (PMID:37683843) and in a USP12/CCL5 axis modulating anti-tumor immunity (PMID:39700963) have also been described.

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 Medium

    Established MPP1 as a scaffolding hub linking distinct polarity and Usher networks, answering how disparate retinal complexes are physically coupled.

    Evidence Interaction and domain-mapping assays with co-localization in retinal tissue, showing directional MAGUK heterodimerization with MPP5/Pals1 and dual-mode binding to whirlin

    PMID:17584769

    Open questions at the time
    • No reconstitution of the multiprotein complex
    • Functional consequence of these interactions for polarity not tested by perturbation
  2. 2009 High

    Defined MPP1 as a spatial regulator of PIP3/Akt signaling required for cell polarity, distinguishing localization control from kinase activity itself.

    Evidence p55 knockout mouse neutrophils with chemotaxis assays, PIP3 immunolocalization, Akt phosphorylation, and PI3Kgamma activity assays

    PMID:19897731

    Open questions at the time
    • Molecular mechanism by which MPP1 restricts PIP3 not resolved
    • Link to raft organization not yet established in this study
  3. 2009 Medium

    Quantified a direct, high-affinity MPP1-merlin interaction, placing MPP1 in cytoskeletal/tumor-suppressor scaffolding contexts beyond erythrocytes.

    Evidence Surface plasmon resonance (KD 3.7 nM) between NF2/merlin FERM domain and erythrocyte p55, with co-localization in Schwann cells

    PMID:19144871

    Open questions at the time
    • Functional consequence of the merlin interaction not tested
    • Single lab, no cellular perturbation
  4. 2012 High

    Identified DHHC17 as the writer of MPP1 palmitoylation and tied this modification causally to membrane order, defining the post-translational requirement for MPP1 raft function.

    Evidence Clinical DHHC17-deficient RBCs, 2-bromopalmitate inhibition, FLIM membrane order, and DRM fractionation

    PMID:22496366

    Open questions at the time
    • Palmitoylation site(s) on MPP1 not mapped
    • Whether DHHC17 acts on MPP1 in non-erythroid cells unknown
  5. 2013 High

    Connected MPP1 levels and palmitoylation to raft-dependent RTK/MAP-kinase signaling, extending the membrane-order role to a signaling output.

    Evidence MPP1 knockdown and palmitoylation inhibition in HEL erythroid cells with DRM fractionation, FLIM, and MAP-kinase assays

    PMID:23507198

    Open questions at the time
    • Which RTKs are affected not enumerated
    • Direct molecular link between MPP1 and the receptors not shown
  6. 2015 Medium

    Demonstrated MPP1 tunes membrane phase behavior directly, showing domain properties depend on the protein rather than lipid composition changes.

    Evidence GPMVs from live cells analyzed for phase separation and miscibility transition temperature

    PMID:25954878

    Open questions at the time
    • Binding partner driving phase modulation not identified in this study
    • Single biophysical method type
  7. 2017 High

    Identified flotillins 1 and 2 as direct MPP1 partners distinct from 4.1-dependent contacts, providing the molecular basis for MPP1's raft-organizing activity.

    Evidence Co-IP and pulldown in erythrocyte membranes plus FLIM membrane fluidity readout

    PMID:28865798

    Open questions at the time
    • Binding interface not yet mapped at this stage
    • Stoichiometry of the complex unknown
  8. 2018 Medium

    Placed MPP1 upstream of H-Ras activation in insulin signaling, linking membrane domain organization to GDP/GTP exchange and effector coupling.

    Evidence MPP1 knockdown in HEL cells with H-Ras GTP-loading and Raf interaction assays plus DRM fractionation under insulin stimulation

    PMID:29719614

    Open questions at the time
    • Mechanism connecting raft order to H-Ras nucleotide exchange not resolved
    • Single cell system
  9. 2021 High

    Localized the flotillin-binding activity to a specific D5 motif and proved its necessity for raft order and insulin signaling via a dominant-negative peptide.

    Evidence Molecular dynamics, SPR affinity measurement, dominant-negative motif-peptide overexpression, FLIM, and insulin receptor signaling assays in erythroid precursors

    PMID:34285255

    Open questions at the time
    • Structure of the full MPP1-flotillin complex not solved
    • Whether the same motif governs non-erythroid functions untested
  10. 2022 High

    Resolved the physical mechanism of raft organization as MPP1-driven immobilization of flotillin nanoclusters and confinement of specific raft lipids.

    Evidence Super-resolution structured illumination imaging, FRAP, and spot-variation FCS in erythroid cells measuring mobility and confinement of sphingomyelin and Thy-1

    PMID:35159121

    Open questions at the time
    • Kinetics of nanocluster capture not detailed
    • Generalizability beyond erythroid cells not tested
  11. 2023 Medium

    Extended MPP1 function to cardiac AGTR1 regulation, showing MPP1 dosage controls receptor protein levels and cardiac physiology.

    Evidence Transgenic MPP1-overexpressing mice with echocardiography and histology, in vivo co-localization, and AGTR1 protein measurement in HEK cells

    PMID:37683843

    Open questions at the time
    • No direct MPP1-AGTR1 binding assay
    • Mechanism of AGTR1 upregulation unknown
  12. 2024 Medium

    Linked MPP1 to immune modulation through a USP12/CCL5 axis affecting T-cell chemotaxis in urothelial carcinoma.

    Evidence Co-IP and mass spectrometry identifying USP12 binding, RT-qPCR/western blot, CD8+ T-cell coculture, and HuNOG tumorigenesis assays

    PMID:39700963

    Open questions at the time
    • How MPP1-USP12 binding drives CCL5 expression not mechanistically resolved
    • Relationship to MPP1's raft-organizing role unclear
  13. 2025 High

    Proved sufficiency: reconstituted MPP1-flotillin assemblies alone generate ordered/disordered domain coexistence in minimal bilayers.

    Evidence Reconstitution of recombinant MPP1 and flotillins in GUVs with FLIM and phase-separation microscopy, with palmitoylation modulating organization

    PMID:41061789

    Open questions at the time
    • Quantitative stoichiometry and structural arrangement in the bilayer not defined
    • How signaling receptors partition into reconstituted domains not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MPP1's raft-organizing scaffold activity is mechanistically reconciled with its discrete roles in AGTR1 regulation and the USP12/CCL5 immune axis remains unresolved.
  • No unified model linking membrane-order function to AGTR1/USP12 phenotypes
  • Structure of MPP1-flotillin complex unsolved
  • Tissue-specificity of partner usage not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
AGTR1FLOT1FLOT2MPP5NF2USP12WHRN

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 MPP1/p55 interacts with MPP5/Pals1 at the outer limiting membrane (OLM) of the retina via heterodimerization of their MAGUK modules in a directional fashion, linking the Usher protein network to the Crumbs polarity complex. Protein interaction assays (binding/interaction studies), co-localization in retina, domain mapping Human molecular genetics Medium 17584769
2007 MPP1 interacts with whirlin (a multi-PDZ scaffold protein of the Usher protein network) via both a classical PDZ domain-to-PDZ binding motif (PBM) mechanism and a mechanism involving internal epitopes; they co-localize at the OLM, outer synaptic layer, basal bodies, and ciliary axoneme in the retina. Protein interaction assays, co-localization by immunofluorescence in retinal tissue Human molecular genetics Medium 17584769
2009 p55/MPP1 knockout neutrophils form multiple transient pseudopods upon chemotactic stimulation and do not migrate efficiently in vitro; upon agonist stimulation, p55 is recruited to the leading edge. In p55(-/-) neutrophils, Akt phosphorylation is significantly decreased and PIP3 is diffusely localized rather than accumulated at the leading edge, despite normal PI3Kgamma activity and normal total PIP3 levels. Thus MPP1 regulates neutrophil polarity by controlling spatial restriction of PIP3 and downstream Akt activation independently of PI3Kgamma. p55 knockout mouse model, chemotaxis assays in vitro, immunofluorescence for PIP3 localization, Akt phosphorylation assays, PI3Kgamma activity immunoprecipitation assay Proceedings of the National Academy of Sciences of the United States of America High 19897731
2009 The FERM domain of NF2/merlin directly binds erythrocyte p55/MPP1 with a KD of 3.7 nM as measured by surface plasmon resonance; both proteins co-localize in non-myelin-forming Schwann cells. Surface plasmon resonance, co-localization by immunofluorescence, monoclonal antibody development Experimental biology and medicine Medium 19144871
2012 DHHC17 is the palmitoylating enzyme (acyltransferase) responsible for MPP1 palmitoylation in red blood cells; loss of DHHC17-mediated palmitoylation of MPP1 results in reduced detergent-resistant membrane (DRM) material and decreased membrane order, linking MPP1 palmitoylation to lateral membrane organization in erythrocytes. Clinical patient RBC analysis (lacking DHHC17), chemical inhibition with 2-bromopalmitic acid, FLIM analysis of membrane order, DRM biochemical fractionation The Journal of biological chemistry High 22496366
2013 MPP1 palmitoylation or MPP1 gene silencing (knockdown) in HEL erythroid precursor cells leads to a dramatic decrease in DRM fraction and reduction in membrane order; MPP1 knockdown also significantly impairs MAP-kinase signaling via raft-dependent RTK receptors. MPP1 gene silencing (knockdown), palmitoylation inhibition, DRM fractionation, FLIM, MAP-kinase signaling assays Biochimica et biophysica acta High 23507198
2015 MPP1 modulates membrane fluidity and phase separation capability of giant plasma membrane-derived vesicles (GPMVs) from live cells, demonstrating that membrane physicochemical domain properties can be tuned by MPP1 protein without major changes in lipid composition. Giant plasma membrane-derived vesicles (GPMVs), fluorescence microscopy of phase separation, miscibility phase transition temperature analysis Biophysical journal Medium 25954878
2017 MPP1 directly binds flotillin 1 and flotillin 2 in erythrocyte membrane; these MPP1-flotillin interactions are distinct from the known protein 4.1-dependent interactions of MPP1. Loss of MPP1-flotillin interactions results in significant changes in RBC membrane fluidity as shown by FLIM, indicating physiological importance for raft domain organization. Multiple protein interaction methods (Co-IP, pulldown), FLIM analysis of membrane fluidity, native RBC membrane complex analysis Biochimica et biophysica acta. Biomembranes High 28865798
2018 MPP1 knockdown in HEL cells impairs insulin receptor signaling specifically at the level of H-Ras, causing impaired GDP-to-GTP exchange and reduced interaction between H-Ras and its effector Raf; H-Ras DRM localization was not sensitive to insulin treatment upon MPP1 knockdown, suggesting MPP1-dependent membrane domain organization is required for H-Ras activation. MPP1 knockdown, H-Ras GTP loading assay, Raf interaction assay, DRM fractionation, insulin stimulation experiments Oncotarget Medium 29719614
2021 High-affinity MPP1-flotillin complexes are formed via a specific 'flotillin binding motif' within the D5 domain of MPP1; overexpression of peptides containing this motif inhibited endogenous MPP1-flotillin interaction in erythroid precursor cells, causing lateral disorganization of raft domains (reduced plasma membrane order) and markedly decreased activation of raft-dependent insulin receptor signaling. Molecular dynamics simulations, surface plasmon resonance, dominant-negative peptide overexpression, membrane order measurement (FLIM), insulin receptor signaling assays Scientific reports High 34285255
2022 MPP1 acts as a key raft-capturing molecule that regulates temporal immobilization of flotillin-based nanoclusters and controls local concentration and confinement of sphingomyelin and Thy-1 in raft nanodomains in erythroid cells, as revealed by super-resolution structured illumination imaging, FRAP, and spot-variation fluorescence correlation spectroscopy (svFCS). Structured illumination microscopy (super-resolution), FRAP, spot-variation FCS (svFCS) Cells High 35159121
2023 MPP1 co-localizes with the angiotensin II AT1 receptor (AGTR1) on sarcolemmal membranes in vivo; transgenic overexpression of MPP1 (2-fold) in mice causes heart failure with reduced ejection fraction, cardiac enlargement and dilation, and increased AGTR1 protein levels. MPP1 also directly increases AGTR1 protein in HEK cells, demonstrating MPP1 can upregulate AGTR1 protein levels. Transgenic mouse model (Tg-MPP1), echocardiography, histology, co-localization in vivo, AGTR1eYFP fluorescence measurement in HEK cells Biochemical pharmacology Medium 37683843
2024 MPP1 binds USP12 (identified by co-immunoprecipitation and mass spectrometry) and promotes CCL5 expression via the MPP1/USP12/CCL5 cascade in urothelial carcinoma cells, thereby enhancing CD8+ T-cell chemotaxis and inhibiting immune escape. Co-immunoprecipitation, mass spectrometry, RT-qPCR, western blotting, MPP1 overexpression vector, CD8+ T-cell coculture assay, in vivo tumorigenesis in HuNOG mice International immunopharmacology Medium 39700963
2025 Reconstituted MPP1 with recombinant flotillins in giant unilamellar vesicles (GUVs) promotes membrane remodeling and triggers coexistence of liquid-ordered (Lo) and liquid-disordered (Ld) domains; palmitoylation of MPP1 exerts additional influence on membrane organization. Flotillin-MPP1 assemblies are sufficient and necessary to modulate lateral organization of lipid bilayers. Reconstitution in GUVs, FLIM, fluorescence microscopy of phase separation with recombinant proteins Biochimica et biophysica acta. Biomembranes High 41061789

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 MPP1 links the Usher protein network and the Crumbs protein complex in the retina. Human molecular genetics 35 17584769
2009 Erythrocyte scaffolding protein p55/MPP1 functions as an essential regulator of neutrophil polarity. Proceedings of the National Academy of Sciences of the United States of America 33 19897731
2012 Palmitoylation of MPP1 (membrane-palmitoylated protein 1)/p55 is crucial for lateral membrane organization in erythroid cells. The Journal of biological chemistry 27 22496366
2013 The role of MPP1/p55 and its palmitoylation in resting state raft organization in HEL cells. Biochimica et biophysica acta 25 23507198
2015 MPP1 as a Factor Regulating Phase Separation in Giant Plasma Membrane-Derived Vesicles. Biophysical journal 23 25954878
2017 MPP1 directly interacts with flotillins in erythrocyte membrane - Possible mechanism of raft domain formation. Biochimica et biophysica acta. Biomembranes 22 28865798
1996 Complete genomic organization of the human erythroid p55 gene (MPP1), a membrane-associated guanylate kinase homologue. Genomics 22 8824805
2000 Autoantibodies from patients with idiopathic ataxia bind to M-phase phosphoprotein-1 (MPP1). Journal of investigative medicine : the official publication of the American Federation for Clinical Research 19 10695267
2015 Cholesterol Interaction with the MAGUK Protein Family Member, MPP1, via CRAC and CRAC-Like Motifs: An In Silico Docking Analysis. PloS one 16 26186446
2012 Repression vs. activation of MOX, FMD, MPP1 and MAL1 promoters by sugars in Hansenula polymorpha: the outcome depends on cell's ability to phosphorylate sugar. FEMS yeast research 16 23164245
2009 Identification of erythrocyte p55/MPP1 as a binding partner of NF2 tumor suppressor protein/Merlin. Experimental biology and medicine (Maywood, N.J.) 13 19144871
2018 The microdomain-organizing protein MPP1 is required for insulin-stimulated activation of H-Ras. Oncotarget 11 29719614
2022 MPP1 Determines the Mobility of Flotillins and Controls the Confinement of Raft-Associated Molecules. Cells 9 35159121
2021 Molecular characterization of direct interactions between MPP1 and flotillins. Scientific reports 9 34285255
2019 MPP1-based mechanism of resting state raft organization in the plasma membrane. Is it a general or specialized mechanism in erythroid cells? Folia histochemica et cytobiologica 9 31099889
2023 Identification of membrane palmitoylated protein 1 (MPP1) as a heart-failure-promoting protein triggered by cardiovascular risk factors and aging. Biochemical pharmacology 6 37683843
2021 High-Level Expression of Palmitoylated MPP1 Recombinant Protein in Mammalian Cells. Membranes 5 34564532
2024 Membrane palmitoylated protein MPP1 inhibits immune escape by regulating the USP12/ CCL5 axis in urothelial carcinoma. International immunopharmacology 4 39700963
1996 cDNA sequence and genomic structure of the murine p55 (Mpp1) gene. Genomics 2 8954807
2025 MPP1 controls lipid domain remodelling in giant vesicles containing reconstituted flotillins. Biochimica et biophysica acta. Biomembranes 1 41061789
2017 MPP1 interacts with DOPC/SM/Cholesterol in an artificial membrane system using Langmuir-Blodgett monolayer. General physiology and biophysics 1 28653654
1994 Identification of a TXREB pseudogene (TXREBP) located between the genes for p55 (MPP1) and G6PD on Xq28. Genomics 1 8088803
2025 Methanol-induced transcription factor Mpp1 regulates the coordinated expression of multiple genes to achieve a balanced C1 metabolism in the methylotrophic yeast Candida boidinii. Microbiology spectrum 0 40162759

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