Affinage

SRP19

Signal recognition particle 19 kDa protein · UniProt P09132

Length
144 aa
Mass
16.2 kDa
Annotated
2026-06-10
24 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SRP19 is an RNA-binding protein that initiates assembly of the signal recognition particle (SRP) by binding the S-domain of 7SL/SRP RNA and preorganizing it for downstream subunit incorporation (PMID:1379233, PMID:12050674). It engages the apical tetraloops of helices 6 and 8 of SRP RNA, with helix 6 serving as the major binding site and recognition occurring at the GGAG tetraloop fold (adenosine 149 being essential) rather than through sequence-specific base contacts (PMID:1711676, PMID:1379233, PMID:12153712). Crystal and NMR structures show SRP19 adopts a rigid RNP-like fold whose N-terminal loop (residues K27, R33, R34) contacts the RNA backbone, clamping helices 6 and 8 into side-by-side packing so that helix 6 acts as a splint that preorganizes the helix 8 internal loop into a conformation competent for high-affinity SRP54 binding (PMID:9182991, PMID:12050674, PMID:12086622, PMID:11916385). This scaffold/chaperone role drives SRP54 incorporation and full SRP assembly (PMID:11041851, PMID:18953414), and the assembled particle mediates co-translational protein secretion, as loss of the SRP19 homolog impairs protein secretion in fungi (PMID:9426009). Genetic and biochemical work confirms an in vivo SRP19–SRP54 functional interaction (PMID:1313948), while SRP19 and SRP68/72 occupy opposite faces of the same helices with anti-cooperative binding (PMID:18564060). SRP19 is rate-limiting for SRP formation: heterozygous loss reduces SRP levels, decreases ER protein translocation/secretion, and elevates ER stress (PMID:40208946). In humans, SRP19 loss-of-function variants cause severe congenital neutropenia by disrupting SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis, impairing neutrophil differentiation (PMID:36223592).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1992 High

    Established that SRP19 is an evolutionarily conserved SRP component that interacts with SRP54 in vivo, anchoring it within the particle's functional architecture.

    Evidence Genetic cloning and multicopy suppressor (epistasis) screen of yeast SEC65/SRP54 in S. cerevisiae

    PMID:1313948

    Open questions at the time
    • Genetic suppression does not define a direct physical contact
    • Does not localize the SRP19–SRP54 interface on the RNA
  2. 1992 High

    Mapped the RNA elements SRP19 recognizes, showing helix 6 is the primary binding site and that recognition is tetraloop-fold-based with additional determinants in helix 8.

    Evidence C-terminal deletion mutagenesis, SRP RNA site-directed mutagenesis, and RNA-protein binding assays (idx 1-4)

    PMID:1379233 PMID:1711676 PMID:1724377 PMID:7517868

    Open questions at the time
    • In vitro binding does not establish in vivo assembly order
    • Functional consequence of binding for SRP54 recruitment not yet shown
  3. 1995 High

    Defined the essential protein regions of SRP19 and showed it binds two RNA conformers cooperatively while inducing conformational change in the RNA large domain.

    Evidence Systematic mutagenesis of human SRP19 plus gel-shift, RNase-sensitivity, and structure-probing assays (idx 5-6)

    PMID:7519610 PMID:7547936

    Open questions at the time
    • Conformational change inferred from probing rather than visualized at atomic resolution
    • Link between induced conformation and SRP54 binding not yet established
  4. 2000 High

    Provided a mechanistic model in which SRP19 binding to helices 6 and 8 remodels the helix 8 bulge into a conformation compatible with high-affinity SRP54 binding, defining its role as an assembly facilitator.

    Evidence Native gel-shift, filter/bead binding, and hydroxyl-radical/DEPC footprinting of A. fulgidus SRP19-RNA complex

    PMID:11041851

    Open questions at the time
    • Conformational model from footprinting predates atomic-resolution confirmation
    • Does not capture the SRP54-bound state directly
  5. 2002 High

    Resolved the structural basis of SRP19 action, showing it clamps the tetraloops of helices 6 and 8 to pack them side by side, with helix 6 acting as a splint that preorganizes the SRP54 binding site.

    Evidence X-ray crystallography of SRP19-RNA complexes and NMR solution structures of SRP19 and helix 6 (idx 10-13)

    PMID:11916385 PMID:12050674 PMID:12086622 PMID:12153712

    Open questions at the time
    • Structures of archaeal proteins with composite RNAs; human holo-SRP assembly intermediate not solved
    • SRP54-bound assembly state not directly captured
  6. 2008 Medium

    Refined the assembly mechanism, showing SRP19 is a rigid scaffold/chaperone that rearranges a single loop via induced fit and binds anti-cooperatively with SRP68/72 on the shared RNA helices.

    Evidence High-resolution crystal structures of free SRP19 and quantitative multi-protein RNA binding assays (idx 15-16)

    PMID:18564060 PMID:18953414

    Open questions at the time
    • Anti-cooperativity measured in vitro with reconstituted components
    • Functional consequence of SRP19/SRP68-72 anti-cooperativity for assembly order not resolved
  7. 2006 High

    Demonstrated that SRP19 is dispensable in at least one archaeon, indicating its essentiality and assembly role are lineage-dependent.

    Evidence Gene deletion in H. volcanii with membrane insertion, secretion, and ribosome assays

    PMID:17071750

    Open questions at the time
    • Dispensability in archaea does not extend to eukaryotic SRP requirements
    • Mechanistic basis for the difference not defined
  8. 2023 High

    Established a human disease link, showing SRP19 loss-of-function causes severe congenital neutropenia by disrupting SRP-dependent protein processing, trafficking, and proteome homeostasis.

    Evidence Human genetics, iPSC-derived neutrophil differentiation, zebrafish models, and proteome analysis

    PMID:36223592

    Open questions at the time
    • Why neutrophil differentiation is selectively vulnerable not fully resolved
    • Allele-specific effects on residual SRP function not detailed
  9. 2025 High

    Showed SRP19 is rate-limiting for SRP formation, so partial loss reduces SRP levels, secretion, and raises ER stress, creating a therapeutic vulnerability in cancer.

    Evidence Knockdown/overexpression in cell lines, animal models, and secretion/ER-stress assays

    PMID:40208946

    Open questions at the time
    • Quantitative threshold of SRP19 limiting SRP assembly in vivo not defined
    • Generality of the arsenic-trioxide vulnerability across tumor contexts not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SRP19-driven RNA remodeling and assembly order integrate within the fully assembled human SRP and translate to cell-type-specific phenotypes remains incompletely defined.
  • No atomic-resolution human holo-SRP assembly intermediate in the corpus
  • Mechanism linking SRP dosage to selective neutrophil vulnerability unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0060090 molecular adaptor activity 3 GO:0044183 protein folding chaperone 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 2
Partners
SRP54SRP68SRP72
Complex memberships
signal recognition particle (SRP)

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The S. cerevisiae SEC65 gene encodes a protein homologous to human SRP19 and is a component of yeast SRP. A multicopy suppressor of sec65-1 was identified as SRP54, providing genetic evidence for an in vivo interaction between SEC65/SRP19 and SRP54. Genetic selection, gene cloning/sequencing, multicopy suppressor screen (epistasis) Nature High 1313948
1991 SRP19 binding to SRP RNA requires a basic region (residues ~113-120, PKLKTRTQ) proximal to the lysine-rich C-terminus; deletion of 14 or 24 C-terminal amino acids still permits RNA binding, but removal of 8 additional residues (positions 113-120) abolishes binding. C-terminal deletion mutagenesis of SRP19, DEAE-Sepharose retention assay for protein-RNA complex Biochemistry and cell biology Medium 1724377
1991 Helix 6 is the major SRP19 binding site on SRP RNA; deletion of helix 6 nearly abolishes SRP19 binding, while deletion of helix 8 retains substantial binding. A construct containing only helices 6, 7, 8, and part of helix 5 fully supports SRP19 binding. Site-directed mutagenesis of SRP RNA, RNA-protein binding assays Nucleic Acids Research Medium 1711676
1992 SRP19 recognizes the tetraloop of helix 6 in SRP RNA in a sequence-specific manner; adenosine 149 at the third tetraloop position is essential for binding. Additional SRP19 binding determinants are located in the distal part of helix 8. Site-directed mutagenesis of SRP RNA tetraloop, RNA-protein binding assays The Journal of Biological Chemistry High 1379233
1994 Specific nucleotides in the 5' portion of the conserved internal loop of helix 8 (positions 192-194, with a pyrimidine at 192 being critical) and three base pairs shaping the helix-8 tetraloop (U195-G204, C196-G203, G197-C202) are required for SRP19 binding; the tetraloop bases of helix 8 themselves are dispensable. Systematic site-directed mutagenesis of SRP RNA helix 8, RNA-protein binding assays European Journal of Biochemistry Medium 7517868
1994 Systematic site-directed mutagenesis of human SRP19 identified five essential regions clustering across the protein sequence; 58% of residues (N/C termini and an internal predicted loop) are dispensable for SRP RNA binding. Systematic site-directed mutagenesis (deletion, pentaglycine substitution, dipeptide alteration) of SRP19, RNA binding assays The Journal of Biological Chemistry High 7519610
1995 Human SRP19 binds two SRP RNA conformers with different affinities (more compact form bound more avidly) and binding is highly cooperative. SRP19 induces conformational changes in the large domain of SRP RNA, and also binds A-form E. coli 5S rRNA, indicating structural similarity between SRP RNA and 5S rRNA. Gel mobility shift assay, RNase sensitivity assay, enzymatic RNA structure probing of SRP19-RNA complex Biochemistry Medium 7547936
1997 A loop in the N-terminal region of SRP19 (containing residues K27, R33, R34) is in direct contact with SRP RNA; mutations K27Q, R33Q, and R34Q impair RNA binding. Alteration of C-terminal basic residues (R83, K116, R118) or deletion of the boundary region did not affect RNA binding. Comparative sequence analysis, proteolytic susceptibility assay, site-directed mutagenesis, RNA binding assays European Journal of Biochemistry Medium 9182991
1997 In Yarrowia lipolytica, SEC65 (SRP19 homolog) co-immunoprecipitates with 7SL RNA, demonstrating stable association within the SRP complex. The two arginine residues of the conserved EGRR motif are essential for SRP activity. Deletion of YlSEC65 is lethal, and temperature-sensitive mutants are defective in protein secretion. Co-immunoprecipitation, site-directed mutagenesis of EGRR motif, gene deletion, temperature-sensitive mutant analysis Gene High 9426009
2000 In Archaeoglobus fulgidus, SRP19 binds the tips of helix 6 and helix 8 of SRP RNA. SRP19 induces conformational changes in the proximal asymmetric bulge of helix 8, presenting it in a conformation compatible with high-affinity SRP54 binding, thereby promoting SRP assembly. Native gel mobility shift, filter binding, Ni-NTA agarose bead binding assays, hydroxyl radical and DEPC chemical modification footprinting Biochemistry High 11041851
2002 Crystal structure of M. jannaschii SRP19 in complex with 7S.S RNA at 2.3 Å: SRP19 bridges the tips of helices 6 and 8, forming an extensive protein-RNA interaction network. This causes helices 6 and 8 to pack side by side, and tertiary RNA interactions (including conserved tetraloop bases) stabilize helix 8 in a conformation competent for SRP54 binding, explaining SRP19's role in facilitating SRP54 incorporation. X-ray crystallography (2.3 Å resolution crystal structure of SRP19-7S.S RNA complex) Nature High 12050674
2002 Crystal structure of M. jannaschii SRP19 with human 7SL S-domain RNA at 2.9 Å: SRP19 clamps the tetraloops of helices 6 and 8, allowing side-by-side packing. Helix 6 acts as a splint for helix 8, partially preorganizing the SRP54 binding site and facilitating SRP54 incorporation. X-ray crystallography (2.9 Å resolution crystal structure of SRP19-S domain RNA complex) Molecular Cell High 12086622
2002 NMR solution structure of A. fulgidus SRP19 reveals a βαββα topology similar to the RNP motif. Unlike canonical RNPs, SRP19 does not engage RNA bases through conserved β-strand motifs; instead, residues within and flanking β-strand 1 contact the phosphate backbone of the tetraloop, leaving tetraloop bases exposed. SRP19 is relatively rigid and undergoes only minor structural changes upon RNA binding. NMR spectroscopy (solution structure determination), site-directed mutagenesis of human SRP19 Journal of Molecular Biology High 11916385
2002 NMR solution structure of SRP RNA helix 6 (29-mer) shows the GGAG tetraloop adopts a GNRA-like conformation. Upon SRP19 binding, the tetraloop becomes more open. SRP19 recognizes the overall fold of the GGAG loop rather than specific bases. NMR spectroscopy of free and SRP19-bound SRP RNA helix 6 Journal of Biochemistry Medium 12153712
2006 Deletion of the SRP19 gene in Haloferax volcanii (Archaea) has no effect on cell growth, membrane protein insertion, protein secretion, or ribosome levels, demonstrating SRP19 is dispensable in this archaeon. Absence of SRP19 increased membrane bacterioruberin levels. Gene deletion in H. volcanii, functional assays for membrane protein insertion, protein secretion, and ribosome levels Journal of Bacteriology High 17071750
2008 Two crystal structures of free Pyrococcus furiosus SRP19 at 1.8 Å reveal a compact, rigid, well-folded protein even without RNA. Comparison with SRP19-RNA complexes shows a disordered loop rearranges upon RNA binding via a reciprocal induced-fit mechanism. SRP19 acts as a molecular scaffold/chaperone assisting SRP RNA in adopting the conformation required for SRP54 binding. X-ray crystallography (two 1.8 Å structures of free SRP19), structural comparison PLoS One High 18953414
2008 SRP19 and SRP68/72 bind opposite faces and ends of the same RNA helices 6 and 8 with moderate anti-cooperativity. SRP19 binds at the apices of helices 6 and 8; SRP68/72 binds at the three-way junction of helices 5, 6, and 8. Both stabilize a parallel orientation of helices 6 and 8, but long-range anti-cooperative binding arises from stabilization of distinct conformations in the intervening RNA scaffold. Quantitative RNA-protein binding assays measuring cooperative/anti-cooperative interactions between SRP19, SRP68, SRP72, and SRP RNA The Biochemical Journal Medium 18564060
2021 Archaeal SRP19 (together with 7S RNA) facilitates and stabilizes the SRP54·FtsY targeting complex, modulating conformation of the targeting complex to reinforce GTP-dependent protein translocation. Fluorescence resonance energy transfer (FRET) assay measuring SRP54·FtsY complex formation in presence/absence of SRP19 and 7S RNA Biochemical and Biophysical Research Communications Medium 34116357
2023 Human SRP19 loss-of-function variants cause severe congenital neutropenia. SRP19 deficiency disrupts SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis, critically impairing neutrophil granulocyte differentiation, as validated in iPSC-derived neutrophils and zebrafish models. Human genetic defect identification, iPSC in vitro differentiation, zebrafish in vivo model, proteome analysis, heterologous cell-based inducible protein expression system Blood High 36223592
2025 SRP19 is rate-limiting for Signal Recognition Particle formation; heterozygous SRP19 loss leads to reduced SRP complex levels, decreased ER protein translocation/secretion, and elevated ER stress, creating a vulnerability exploitable by low-dose arsenic trioxide treatment in APC-deleted cancer cells. Knockdown/overexpression in cultured cell lines, animal models, protein secretion assays, ER stress assays Proceedings of the National Academy of Sciences of the United States of America High 40208946

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 The S. cerevisiae SEC65 gene encodes a component of yeast signal recognition particle with homology to human SRP19. Nature 94 1313948
2002 Structure of the SRP19 RNA complex and implications for signal recognition particle assembly. Nature 84 12050674
2002 Crystal structure of SRP19 in complex with the S domain of SRP RNA and its implication for the assembly of the signal recognition particle. Molecular cell 58 12086622
1992 Recognition of a tetranucleotide loop of signal recognition particle RNA by protein SRP19. The Journal of biological chemistry 58 1379233
2000 Role of SRP19 in assembly of the Archaeoglobus fulgidus signal recognition particle. Biochemistry 55 11041851
1991 Interaction of protein SRP19 with signal recognition particle RNA lacking individual RNA-helices. Nucleic acids research 50 1711676
2008 Structures of SRP54 and SRP19, the two proteins that organize the ribonucleic core of the signal recognition particle from Pyrococcus furiosus. PloS one 23 18953414
1994 Site-directed mutagenesis of signal-recognition particle RNA. Identification of the nucleotides in helix 8 required for interaction with protein SRP19. European journal of biochemistry 23 7517868
2023 Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes. Blood 21 36223592
1995 Cooperative assembly of signal recognition particle RNA with protein SRP19. Biochemistry 20 7547936
2002 Solution structure of protein SRP19 of Archaeoglobus fulgidus signal recognition particle. Journal of molecular biology 18 11916385
1994 Systematic site-directed mutagenesis of protein SRP19. Identification of the residues essential for binding to signal recognition particle RNA. The Journal of biological chemistry 17 7519610
2006 SRP19 is a dispensable component of the signal recognition particle in Archaea. Journal of bacteriology 16 17071750
2002 Solution structure of a SRP19 binding domain in human SRP RNA. Journal of biochemistry 14 12153712
1997 Isolation and cloning of the Yarrowia lipolytica SEC65 gene, a component of the yeast signal recognition particle displaying homology with the human SRP19 gene. Gene 9 9426009
1991 A basic region neighboring the lysine-rich C-terminus of protein SRP19 is required for binding to signal recognition particle RNA. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 1724377
1997 Identification of an RNA-binding-loop in the N-terminal region of signal-recognition-particle protein SRP19. European journal of biochemistry 7 9182991
2016 Expression of anti-SRP19 antibody in muscle tissues from patients with autoimmune necrotizing myopathy. Genetics and molecular research : GMR 5 27525944
2008 Anti-cooperative assembly of the SRP19 and SRP68/72 components of the signal recognition particle. The Biochemical journal 5 18564060
2011 Compositional and structural features related to thermal stability in the archaea SRP19 and SRP54 signal recognition particle proteins. Journal of molecular evolution 4 21505884
1997 Interaction of rice and human SRP19 polypeptides with signal recognition particle RNA. Plant molecular biology 3 9225861
2021 Archaeal SRP RNA and SRP19 facilitate the assembly of SRP54-FtsY targeting complex. Biochemical and biophysical research communications 2 34116357
2025 SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss. Proceedings of the National Academy of Sciences of the United States of America 1 40208946
2009 Characterization of RNA aptamers against SRP19 protein having sequences different from SRP RNA. Nucleic acids symposium series (2004) 1 19749362

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