Affinage

LRPAP1

Alpha-2-macroglobulin receptor-associated protein · UniProt P30533

Round 2 corrected
Length
357 aa
Mass
41.5 kDa
Annotated
2026-04-28
130 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRPAP1 (RAP) is a specialized endoplasmic reticulum-resident molecular chaperone that escorts newly synthesized members of the LDL receptor family—including LRP, megalin/gp330, SorLA, and VLDLR—through the secretory pathway by competitively occupying their ligand-binding sites, thereby preventing premature ligand-induced aggregation and degradation (PMID:7774585, PMID:8654360). RAP binds LRP at two equivalent high-affinity sites (KD ~14 nM) and is retained in the ER via its C-terminal HNEL tetrapeptide recognized by ERD2/KDEL receptors; pH-dependent dissociation later in the secretory pathway restores receptor ligand-binding competence (PMID:1374383, PMID:9010785). RAP-knockout mice exhibit reduced mature LRP in liver and brain, impaired alpha-2-macroglobulin clearance, and remnant lipoprotein accumulation, confirming its essential in vivo chaperone function (PMID:7538675, PMID:8654360). Secreted LRPAP1 also has an extracellular role: its N-terminus binds IFNAR1, triggering ubiquitination-dependent receptor degradation that suppresses type I interferon signaling and facilitates viral immune evasion (PMID:37743411).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1991 High

    Identification of RAP as a direct LRP-binding protein that modulates receptor ligand-binding activity established the first functional connection between this 39-kDa protein and lipoprotein receptor biology.

    Evidence Recombinant fusion protein binding assays and ligand uptake inhibition in cultured cells; concurrent cDNA cloning with pulse-chase and cell surface labeling

    PMID:1712782 PMID:1718973

    Open questions at the time
    • Binding stoichiometry and affinity not yet determined
    • Physiological relevance (intracellular vs. surface function) unresolved
    • No data on other LDL receptor family members
  2. 1992 High

    Quantitative binding analysis revealed RAP occupies two equivalent high-affinity sites on LRP (KD ~14 nM), with progressive saturation of these sites completely ablating ligand binding, resolving how RAP stoichiometrically controls receptor activity.

    Evidence Titration binding and heterologous displacement assays with purified LRP on fibroblasts

    PMID:1374383

    Open questions at the time
    • Structural basis of two-site binding unknown
    • Whether RAP acts inside the cell or at the surface still debated
  3. 1994 High

    Domain mapping identified two distinct megalin/gp330-binding domains and a separate heparin-binding domain in RAP, demonstrating modular architecture that enables interaction with multiple receptors.

    Evidence GST fusion protein binding studies, ligand blotting, and heparin-binding assays

    PMID:7512726

    Open questions at the time
    • Whether domain modularity dictates receptor selectivity in vivo unresolved
    • Structural basis of domain-receptor interactions not determined
  4. 1995 High

    Three converging lines of evidence—ER localization via the HNEL retention signal, pH-dependent dissociation from LRP, and RAP-knockout mouse phenotype—established RAP as an ER-resident molecular chaperone essential for functional maturation and surface delivery of LDL receptor family members.

    Evidence C-terminal mutagenesis of HNEL, cross-linking and pulse-chase in the secretory pathway, gene-targeted RAP-null mice with reduced LRP and impaired alpha-2-macroglobulin clearance; parallel studies on megalin chaperoning

    PMID:7538675 PMID:7579068 PMID:7774585

    Open questions at the time
    • Whether RAP directly assists receptor folding (vs. only blocking ligands) not distinguished
    • Structural basis of pH-dependent dissociation unknown
  5. 1996 High

    Rescue experiments in RAP-null fibroblasts demonstrated that RAP prevents co-expressed ligands (apoE) from binding newly synthesized LRP in the ER, causing aggregation and degradation—defining RAP as a competitive antagonist-type chaperone specific to endocytic receptors. RAP affinity chromatography also identified SorLA (SORL1) as a new binding partner.

    Evidence ApoE overexpression with/without RAP co-expression in RAP-null embryonic fibroblasts; RAP affinity purification from human brain identifying SorLA

    PMID:8654360 PMID:8940146

    Open questions at the time
    • Full repertoire of RAP client receptors not mapped
    • Physiological consequences of SorLA–RAP interaction not tested in vivo
  6. 1997 High

    The ER retention mechanism was resolved: ERD2 (KDEL receptor) isoforms recognize the non-canonical HNEL signal of RAP, and saturation of ERD2 capacity causes RAP secretion and consequent ~60% loss of functional LRP, quantifying the dependence of receptor biogenesis on the retrieval cycle.

    Evidence ERD2 overexpression, immunoelectron microscopy, pulse-chase with GH-HNEL/KDEL reporter constructs

    PMID:9010785

    Open questions at the time
    • Whether ERD2 isoforms show preferential specificity for HNEL vs. KDEL in vivo not determined
    • Consequences of physiological RAP secretion not explored
  7. 2004 High

    Circulating RAP was shown to cross the blood-brain barrier via a saturable, megalin-dependent transcytosis process, with the majority reaching brain parenchyma—revealing a potential extracellular trafficking function beyond ER chaperoning.

    Evidence Radiolabeled RAP pharmacokinetics in mice, in situ brain perfusion, capillary depletion, polarized MDCK transcytosis assays

    PMID:15383619

    Open questions at the time
    • Physiological significance of blood-borne RAP in the brain not established
    • Whether BBB-transported RAP modulates neuronal LRP function in vivo unknown
  8. 2023 High

    A previously unrecognized extracellular function was discovered: secreted LRPAP1, upregulated by viral proteases, binds IFNAR1 via its N-terminus, triggers ubiquitination and degradation of the interferon receptor, and suppresses innate immunity—establishing LRPAP1 as a host factor exploited for viral immune evasion.

    Evidence Co-IP of LRPAP1 with IFNAR1, ubiquitination assays, peptide competition, alpha-2-macroglobulin rescue, multi-virus infection assays in vitro and in vivo (newborn mice)

    PMID:37743411

    Open questions at the time
    • Whether IFNAR1 degradation by LRPAP1 occurs during non-infectious physiology unknown
    • Structural basis of LRPAP1 N-terminus–IFNAR1 interaction not determined
    • Whether other interferon receptor subunits are affected not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether RAP directly assists folding of LDL receptor cysteine-rich repeats (beyond competitive ligand blocking), the structural basis of pH-dependent receptor dissociation, and the physiological scope of the newly discovered extracellular IFNAR1-degradation function outside viral infection contexts.
  • No high-resolution structure of a full RAP–receptor complex exists
  • Direct folding chaperone activity vs. competitive shielding not experimentally separated
  • IFNAR1 degradation pathway not yet confirmed by independent laboratories

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005576 extracellular region 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 1 R-HSA-168256 Immune System 1
Partners
IFNAR1KDELR1KDELR2LRP1LRP2SORL1SORT1

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The 39-kDa receptor-associated protein (RAP/LRPAP1) binds directly to the 515-kDa subunit of LRP/alpha2-macroglobulin receptor and inhibits binding and uptake of both beta-migrating VLDL (apoE-enriched) and activated alpha2-macroglobulin, demonstrating that RAP modulates receptor ligand-binding activity. Recombinant fusion protein binding assay, ligand uptake inhibition assay in cells The Journal of biological chemistry High 1718973
1991 LRPAP1 (RAP) primary structure was determined by cDNA cloning, revealing a 323-residue mature protein with 73% identity to rat Heymann nephritis antigen and 77% identity to mouse HBP-44; pulse-chase experiments showed newly formed RAP remains cell-associated, and surface labeling showed RAP forms a complex with the alpha2M receptor heavy and light chains on the cell surface. cDNA cloning, pulse-chase radiolabeling, cell surface labeling and immunoprecipitation The Journal of biological chemistry High 1712782
1992 RAP binds to two equivalent sites on LRP/alpha2MR with a KD of 14 nM; as RAP-binding sites are saturated, LRP completely loses the ability to bind ligands (Ki ~23–26 nM for inhibition of alpha2M binding), indicating that the number of RAP molecules bound dictates receptor activity. A model was proposed in which LRP contains multiple ligand-binding sites, each regulated by a separate RAP-binding site. Titration binding studies, heterologous ligand displacement assays with purified LRP and on human fibroblasts The Journal of biological chemistry High 1374383
1994 RAP contains two distinct gp330/megalin-binding sites (amino acids 85–148 and 178–248) and a separate heparin-binding site (amino acids 261–323), demonstrating that the gp330-binding, heparin-binding, and Heymann nephritis pathogenic epitope (aa 1–86) domains are functionally distinct. Direct binding studies using GST fusion proteins representing overlapping RAP domains, ligand blotting, affinity chromatography, density-gradient sedimentation, radiolabeled heparin binding Proceedings of the National Academy of Sciences of the United States of America High 7512726
1994 Immunohistochemical mapping in rat organs showed RAP is found in intracellular vesicles in all cells expressing gp330 or LRP, and is not definitively detected on the cell surface, indicating its major physiological function is intracellular (assembly/trafficking of receptors). RAP binding sites were found on cell surfaces where surface gp330 or LRP is expressed. Immunohistochemistry with organ distribution mapping; exogenous RAP binding experiments in vivo The journal of histochemistry and cytochemistry Medium 7510321
1995 RAP is an endoplasmic reticulum (ER) resident protein; the C-terminal tetrapeptide HNEL is both necessary and sufficient for ER retention. RAP interacts with LRP in vivo (demonstrated by cross-linking), the association is transient and occurs early in the secretory pathway, and dissociation at lower pH later in the pathway correlates with increased LRP ligand-binding activity. RAP functions as a molecular chaperone for LRP, preventing ligand-induced aggregation and maintaining LRP in a ligand-binding competent state. Metabolic labeling, cross-linking, pulse-chase analysis, C-terminal deletion/mutation analysis of HNEL signal, transfection of HNEL-tagged reporter proteins The EMBO journal High 7774585
1995 Gene targeting (RAP-knockout mice) demonstrated that RAP is required for functional expression of LRP in vivo: RAP-deficient mice show reduced mature LRP in liver and brain, impaired hepatic clearance of alpha2-macroglobulin, and accumulation of remnant lipoproteins in plasma (in LDL receptor-null background), confirming RAP stabilizes LRP within the secretory pathway. Gene targeting/knockout mouse model, LRP immunoblotting, alpha2M clearance assay, plasma lipoprotein analysis Proceedings of the National Academy of Sciences of the United States of America High 7538675
1995 RAP was identified as a component of the Heymann nephritis antigenic complex; it associates with megalin (gp330) and functions as a chaperone assisting in megalin folding in the ER and its transport to the cell surface. Binding to megalin is Ca2+-dependent (also shown in Orlando & Farquhar 1994). Biochemical characterization, ligand blotting, immunocytochemistry, affinity chromatography Journal of the American Society of Nephrology High 7579068
1996 RAP-deficient mice generated by gene targeting showed that RAP prevents premature binding of co-expressed ligands (e.g., apoE) to newly synthesized LRP and other LDL receptor family members in the ER, preventing ligand-induced aggregation and degradation. Overexpression of apoE dramatically reduced cellular LRP expression, an effect prevented by RAP co-expression, establishing RAP as a specialized chaperone class that selectively protects endocytic receptors. Gene targeting (RAP-null mice), apoE overexpression rescue experiments, LRP expression analysis, embryonic fibroblast studies The EMBO journal High 8654360
1997 ERD2 proteins (ERD2.1 and ERD2.2, the mammalian KDEL receptors) mediate ER retention of RAP via its novel C-terminal HNEL signal. Overexpression of GH tagged with HNEL or KDEL both saturated ER retention receptors and caused secretion of endogenous RAP. Overexpression of either ERD2 isoform significantly increased the retention capacity for both KDEL- and HNEL-containing proteins, and functional LRP was reduced ~60% when intracellular RAP was decreased. Immunoelectron microscopy, stable transfection of GH-HNEL and GH-KDEL constructs, pulse-chase labeling, ERD2 overexpression, immunolocalization Journal of cell science High 9010785
1997 RAP affinity chromatography from human brain extracts purified a novel ~95-kDa membrane glycoprotein (gp95/sortilin), demonstrating that LRPAP1 can be used as an affinity ligand to identify novel receptors beyond the canonical LDL receptor family, and that sortilin is a RAP-binding protein. RAP affinity chromatography, protein purification from human brain, cDNA cloning The Journal of biological chemistry Medium 9013611
1996 RAP affinity chromatography purified a novel ~250-kDa brain protein (sorLA-1/SORL1), a hybrid receptor containing both Vps10p-homologous domains and LDL receptor family repeats, demonstrating LRPAP1 binds this receptor and validating RAP as a tool to identify LDL receptor family-related proteins. RAP affinity chromatography from human brain, cDNA cloning, Northern blotting The Journal of biological chemistry Medium 8940146
1998 RAP is defined as a novel class of molecular chaperone specifically designed to assist biosynthesis of endocytic receptors of the LDL receptor family; it acts as a receptor antagonist in the secretory pathway, preventing premature receptor-ligand association in cell types that co-express both receptor and ligand, thereby ensuring proper receptor export to the cell surface. Review synthesizing experimental evidence from multiple studies including RAP-null mice, ER localization, and ligand binding inhibition experiments Biological chemistry High 9792434
2000 RAP's role in biogenesis of lipoprotein receptors was established: RAP serves as a molecular chaperone assisting folding of lipoprotein receptors and their safe passage through the secretory pathway. Multiple non-exclusive models were proposed: (1) RAP competitively inhibits ligand binding by occupying ligand-binding sites, and (2) RAP may directly assist folding of the cysteine-rich ligand-binding repeats. Review of experimental evidence; biochemical studies of RAP-receptor interactions in secretory pathway Trends in cardiovascular medicine Medium 11239794
2004 Blood-borne RAP crosses the blood-brain barrier (BBB) by a saturable transport process; ~70% of transported RAP localizes in brain parenchyma rather than vasculature. Transport across polarized epithelial cell monolayers (MDCK) is consistent with megalin (LRP2) mediating most apical-to-basolateral transcytosis. Inhibition by excess RAP and involvement of megalin indicate a specific saturable transport system at the BBB. [125I]-RAP pharmacokinetics in intact mice, in situ brain perfusion, capillary depletion of brain homogenates, transport assays in stably transfected polarized MDCK cell monolayers Journal of cell science High 15383619
2007 Recombinant RAP was successfully expressed in E. coli using pT7-PL vector in BL21(DE3,plysS) strain with optimal conditions (chloramphenicol selection), and purified RAP retained functional binding to RAW264.7 macrophage cells (which are rich in LDL receptor family members), confirming that recombinant RAP binds LDL receptor family receptors. Prokaryotic expression in E. coli, Ni-NTA affinity purification, cell binding assay with RAW264.7 macrophages Journal of Huazhong University of Science and Technology. Medical sciences Medium 17393096
2018 LRPAP1-reactive B-cell receptors (BCRs) in mantle cell lymphoma (MCL) recognize LRPAP1 as a proliferation-inducing autoantigen; LRPAP1 stimulation activates the BCR signaling pathway in MCL cells. An LRPAP1-ETA' immunotoxin conjugate specifically killed MCL cells bearing LRPAP1-reactive BCRs, demonstrating that LRPAP1 can trigger BCR pathway signaling and be used for targeted therapy. Recombinant BCR expression, antigen screening, LRPAP1-induced proliferation assay, BCR pathway activation assay, immunotoxin killing assay Leukemia Medium 29955130
2023 Secreted LRPAP1 (upregulated by viral proteases SARS-CoV-2 3CLpro and EV71 2Apro) binds via its N-terminus to the extracellular domain of IFNAR1 (interferon-alpha/beta receptor 1), triggering IFNAR1 ubiquitination and degradation, thereby suppressing innate immune signaling and facilitating viral infection. A small N-terminal LRPAP1 peptide recapitulated IFNAR1 degradation and enhanced infection by multiple viruses (HSV-1, HBV, EV71, HCoV-OC43); alpha2M (a LRPAP1 inhibitor) stabilized IFNAR1 and arrested viral infections. Viral protease overexpression, ELISA/Western blot for LRPAP1 secretion, co-IP of LRPAP1 with IFNAR1 extracellular domain, IFNAR1 ubiquitination assay, viral infection assays in vitro/ex vivo (mouse brain)/in vivo (newborn mice), peptide competition, alpha2M inhibition Signal transduction and targeted therapy High 37743411
2001 Genetic variation at the LRPAP1 locus (intron 5 insertion/deletion polymorphism) is associated with late-onset Alzheimer disease risk; homozygosity for the rare insertion allele was significantly underrepresented in patients vs. controls (OR=0.29), suggesting LRPAP1 variation modulates disease risk, consistent with its role in LRP-mediated amyloid-beta clearance pathway. Genotyping of LRPAP1 I/D polymorphism by PCR in 373 patients and 400 controls, logistic regression analysis American journal of medical genetics Low 11425005

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The sequence of the human genome. Science (New York, N.Y.) 8428 11181995
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1988 Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. The EMBO journal 918 3266596
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1999 Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 774 10571241
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 648 12202034
2004 Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proceedings of the National Academy of Sciences of the United States of America 618 15342917
1991 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. The Journal of biological chemistry 543 1718973
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2005 Linking Rap to cell adhesion. Current opinion in cell biology 389 15780587
1997 Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. The Journal of biological chemistry 359 9013611
2015 Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nature neuroscience 352 26005850
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1992 A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. The Journal of biological chemistry 311 1374383
1994 Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 299 7510321
2001 A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nature cell biology 285 11715024
1995 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. The EMBO journal 280 7774585
1996 RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. The EMBO journal 247 8654360
1995 Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proceedings of the National Academy of Sciences of the United States of America 247 7538675
1996 Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein. The Journal of biological chemistry 230 8940146
1991 Primary structure of alpha 2-macroglobulin receptor-associated protein. Human homologue of a Heymann nephritis antigen. The Journal of biological chemistry 229 1712782
2008 SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nature cell biology 226 19098903
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2000 The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. The Journal of biological chemistry 185 10747918
1995 The Heymann nephritis antigenic complex: megalin (gp330) and RAP. Journal of the American Society of Nephrology : JASN 183 7579068
2004 Putting the rap on Akt. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 178 15483033
2003 Does Rap1 deserve a bad Rap? Trends in biochemical sciences 171 12765839
2008 Specificity in Ras and Rap signaling. The Journal of biological chemistry 149 19091745
2003 The extracellular Phr peptide-Rap phosphatase signaling circuit of Bacillus subtilis. Frontiers in bioscience : a journal and virtual library 138 12456319
2012 Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Science signaling 137 22253263
2010 Ras and Rap signaling in synaptic plasticity and mental disorders. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 127 20431046
2008 Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection. Journal of cellular physiology 126 18064650
2011 Regulating Rap small G-proteins in time and space. Trends in cell biology 125 21820312
2003 The Rap GTPases regulate integrin-mediated adhesion, cell spreading, actin polymerization, and Pyk2 tyrosine phosphorylation in B lymphocytes. The Journal of biological chemistry 118 14701796
1996 RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein. Oncogene 117 8710374
2004 Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier. Journal of cell science 107 15383619
2004 ARAP3 is a PI3K- and rap-regulated GAP for RhoA. Current biology : CB 103 15296756
1991 The residues of Ras and Rap proteins that determine their GAP specificities. The Journal of biological chemistry 102 1828804
2011 Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cellular signalling 100 21402149
2004 Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway. Journal of virology 96 15047839
2014 Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Investigative ophthalmology & visual science 93 25525168
1997 The rap and hor proteins of Erwinia, Serratia and Yersinia: a novel subgroup in a growing superfamily of proteins regulating diverse physiological processes in bacterial pathogens. Molecular microbiology 92 9402023
2006 Rap-GEF signaling controls stem cell anchoring to their niche through regulating DE-cadherin-mediated cell adhesion in the Drosophila testis. Developmental cell 89 16399083
2011 Cofilin-mediated F-actin severing is regulated by the Rap GTPase and controls the cytoskeletal dynamics that drive lymphocyte spreading and BCR microcluster formation. Journal of immunology (Baltimore, Md. : 1950) 83 22068232
2011 Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. Neuron 82 21382555
2001 Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras. The Journal of biological chemistry 80 11524421
2011 Structural basis of response regulator dephosphorylation by Rap phosphatases. PLoS biology 79 21346797
2018 RAP-MS: A Method to Identify Proteins that Interact Directly with a Specific RNA Molecule in Cells. Methods in molecular biology (Clifton, N.J.) 76 29130217
2020 Genetic modulation of RAP alters fruit coloration in both wild and cultivated strawberry. Plant biotechnology journal 74 31845477
1998 Electrostatic contributions to protein-protein binding affinities: application to Rap/Raf interaction. Proteins 73 9533625
1997 Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle. Cell motility and the cytoskeleton 73 9295142
2015 RNA antisense purification (RAP) for mapping RNA interactions with chromatin. Methods in molecular biology (Clifton, N.J.) 72 25555582
2008 Highlighting the role of Ras and Rap during Dictyostelium chemotaxis. Cellular signalling 68 18385017
2006 GAP1 family members constitute bifunctional Ras and Rap GTPase-activating proteins. The Journal of biological chemistry 66 16431904
2005 Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration. Current opinion in hematology 65 15604886
2012 Afadin, a Ras/Rap effector that controls cadherin function, promotes spine and excitatory synapse density in the hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 64 22219273
1994 Functional domains of the receptor-associated protein (RAP). Proceedings of the National Academy of Sciences of the United States of America 64 7512726
1998 Receptor-associated protein (RAP): a specialized chaperone for endocytic receptors. Biological chemistry 63 9792434
2013 Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin. eLife 62 24137545
2018 Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains. Neuron 61 29706584
2014 RAP, the sole octotricopeptide repeat protein in Arabidopsis, is required for chloroplast 16S rRNA maturation. The Plant cell 61 24585838
2005 RA-RhoGAP, Rap-activated Rho GTPase-activating protein implicated in neurite outgrowth through Rho. The Journal of biological chemistry 60 16014623
2007 A Wnt-CKIvarepsilon-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein. Developmental cell 58 17336901
1992 Inhibitory monoclonal antibodies recognise epitopes adjacent to a proteolytic cleavage site on the RAP-1 protein of Plasmodium falciparum. Molecular and biochemical parasitology 55 1279419
2013 Conformational change-induced repeat domain expansion regulates Rap phosphatase quorum-sensing signal receptors. PLoS biology 53 23526881
2000 Role of rap in the biogenesis of lipoprotein receptors. Trends in cardiovascular medicine 53 11239794
1998 Structure, sequence, and transcriptional analysis of the Babesia bovis rap-1 multigene locus. Molecular and biochemical parasitology 53 9662706
2013 Structural basis of Rap phosphatase inhibition by Phr peptides. PLoS biology 52 23526880
2008 cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics. Cellular signalling 51 18346875
2006 Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Archives of general psychiatry 50 16754837
2017 FASTKD1 and FASTKD4 have opposite effects on expression of specific mitochondrial RNAs, depending upon their endonuclease-like RAP domain. Nucleic acids research 49 28335001
2003 New N-RAP-binding partners alpha-actinin, filamin and Krp1 detected by yeast two-hybrid screening: implications for myofibril assembly. Journal of cell science 49 12692149
1999 Molecular interactions of N-RAP, a nebulin-related protein of striated muscle myotendon junctions and intercalated disks. Biochemistry 49 10320340
2008 A novel Epac-Rap-PP2A signaling module controls cAMP-dependent Akt regulation. The Journal of biological chemistry 48 18550542
2010 Sequence heterogeneity in the gene encoding the rhoptry-associated protein-1 (RAP-1) of Babesia caballi isolates from South Africa. Veterinary parasitology 47 20138703
2004 RAP--a putative RNA-binding domain. Trends in biochemical sciences 47 15501674
2001 Ultrastructural and biochemical localization of N-RAP at the interface between myofibrils and intercalated disks in the mouse heart. Biochemistry 46 11732910
1997 Genetic variation in the dimorphic regions of RAP-1 genes and rap-1 loci of Babesia bigemina. Molecular and biochemical parasitology 46 9476795
2003 Activation of the Rap GTPases in B lymphocytes modulates B cell antigen receptor-induced activation of Akt but has no effect on MAPK activation. The Journal of biological chemistry 45 12904304
2002 Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice. Molecular and cellular biology 44 11839810
2010 RapGAPs in brain: multipurpose players in neuronal Rap signalling. The European journal of neuroscience 43 20576033
2001 Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease. American journal of medical genetics 42 11425005
2011 Epac-Rap signaling reduces cellular stress and ischemia-induced kidney failure. Journal of the American Society of Nephrology : JASN 41 21493776
2010 A Rap/phosphatidylinositol 3-kinase pathway controls pseudopod formation [corrected]. Molecular biology of the cell 41 20089846
1994 gp330 and RAP: the Heymann nephritis antigenic complex. Annals of the New York Academy of Sciences 41 7944157
2014 The Ras/Rap GTPase activating protein RASA3: from gene structure to in vivo functions. Advances in biological regulation 38 25294679
2006 The Rap GTPases mediate CXCL13- and sphingosine1-phosphate-induced chemotaxis, adhesion, and Pyk2 tyrosine phosphorylation in B lymphocytes. European journal of immunology 38 16821235
2018 RAP GTPases and platelet integrin signaling. Platelets 37 29863951
2005 The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells. Diabetologia 37 15995848
2019 Astragalus Polysaccharide RAP Selectively Attenuates Paclitaxel-Induced Cytotoxicity Toward RAW 264.7 Cells by Reversing Cell Cycle Arrest and Apoptosis. Frontiers in pharmacology 35 30804792
2007 The Rap GTPase activator Drosophila PDZ-GEF regulates cell shape in epithelial migration and morphogenesis. Molecular and cellular biology 35 17846121
1997 ERD2 proteins mediate ER retention of the HNEL signal of LRP's receptor-associated protein (RAP). Journal of cell science 35 9010785
2017 Development of RAP Tag, a Novel Tagging System for Protein Detection and Purification. Monoclonal antibodies in immunodiagnosis and immunotherapy 34 28339303
2014 Molecular characterization of the Babesia caballi rap-1 gene and epidemiological survey in horses in Israel. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 34 24524984
1998 Analysis of inhibitory epitopes in the Plasmodium falciparum rhoptry protein RAP-1 including identification of a second inhibitory epitope. Infection and immunity 33 9423886
2007 Optimal expression condition of recombinant RAP. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 31 17393096
2014 RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice. American journal of hematology 30 25236856
1994 Interstrain conservation of babesial RAP-1 surface-exposed B-cell epitopes despite rap-1 genomic polymorphism. Infection and immunity 30 7518810
2015 A plasmid-born Rap-Phr system regulates surfactin production, sporulation and genetic competence in the heterologous host, Bacillus subtilis OKB105. Applied microbiology and biotechnology 29 25921807
2009 Myofibril assembly visualized by imaging N-RAP, alpha-actinin, and actin in living cardiomyocytes. Experimental cell research 29 19233165
2004 Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for epithelial integrity. Molecular biology of the cell 29 15525675
2008 Spa-1 (Sipa1) and Rap signaling in leukemia and cancer metastasis. Cancer science 28 19037996
2017 The role of small GTPases and EPAC-Rap signaling in the regulation of the blood-brain and blood-retinal barriers. Tissue barriers 27 28632993
2009 Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice. Neuroscience 27 19442707
2000 Myofibrillogenesis and formation of cell contacts mediate the localization of N-RAP in cultured chick cardiomyocytes. Cell motility and the cytoskeleton 27 11002311
2013 Rap G protein signal in normal and disordered lymphohematopoiesis. Experimental cell research 26 23603280
2010 Enhanced cartilage regeneration in MIA/CD-RAP deficient mice. Cell death & disease 26 21368873
1998 Platelet sarco/endoplasmic reticulum Ca2+ATPase isoform 3b and Rap 1b: interrelation and regulation in physiopathology. The Biochemical journal 26 9576865
2021 Epac-1/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia/reperfusion model. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 33957564
2014 APOE and LRPAP1 gene polymorphism and risk of Parkinson's disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 25 24504617
2009 The Rap GTPases regulate the migration, invasiveness and in vivo dissemination of B-cell lymphomas. Oncogene 25 19838206
2018 Rapeseed protein-derived antioxidant peptide RAP alleviates renal fibrosis through MAPK/NF-κB signaling pathways in diabetic nephropathy. Drug design, development and therapy 24 29795979
2008 Expression and alternative splicing of N-RAP during mouse skeletal muscle development. Cell motility and the cytoskeleton 24 18792955
2018 Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap. International journal of molecular sciences 23 29659486
2018 LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting. Leukemia 23 29955130
2018 How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma. Hepatic oncology 23 30302196
1989 Expression of the ras-related rap genes in human tumors. International journal of cancer 23 2514150
2023 Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity. Signal transduction and targeted therapy 22 37743411
2007 Rac and Rap GTPase activation assays. Methods in molecular biology (Clifton, N.J.) 22 18453105
1996 RAP kinase, a new enzyme phosphorylating the acidic P proteins from Saccharomyces cerevisiae. Biochimica et biophysica acta 22 8620032