Affinage

SRP68

Signal recognition particle subunit SRP68 · UniProt Q9UHB9

Length
627 aa
Mass
70.7 kDa
Annotated
2026-06-10
35 papers in source corpus 16 papers cited in narrative 16 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

SRP68 is the RNA-binding scaffold subunit of the signal recognition particle (SRP) S domain, functioning together with SRP72 to remodel SRP (7SL) RNA into a conformation competent for co-translational protein targeting to the ER (PMID:8388879, PMID:17254600). The SRP68/72 heterodimer binds SRP RNA directly and specifically with high affinity, associating with a distinct RNA domain independently of the SRP9/14 (Alu) module (PMID:1377027). SRP68 makes the primary RNA contact through its N-terminal RNA-binding domain (residues ~52–252), while a C-terminal peptide links the particle to SRP72; SRP72 cannot bind RNA on its own and requires both 7S RNA and SRP68 for incorporation, so SRP68 acts as the obligatory bridge between RNA and SRP72 (PMID:8388879, PMID:16672232). Crystallographic work established that the SRP68 RNA-binding domain is a tetratricopeptide-like module that binds an RNA three-way junction, bends the RNA, and inserts an arginine-rich α-helical motif into the major groove to open the conserved 5f loop that contacts ribosomal RNA in ribosome-bound SRP (PMID:24700861), while SRP68/72 binding draws helices 6 and 8 together and protects the SRP54-binding site, rearranging the RNA into an SRP54-competent state (PMID:17254600). The reconstituted heterodimer binds the ribosome with ultrasensitive avidity through multiple contact sites, an interaction SRP RNA alone cannot make (PMID:30649417), and a full-length structure reveals an extended dimerization domain that, upon SRP docking onto the SRP receptor, repositions near the Alu domain and is implicated in releasing elongation arrest (PMID:38366771). Genetically, SRP68 is required for stable SRP assembly and efficient ER translocation: its loss in yeast destabilizes the entire particle and impairs protein translocation (PMID:7925282). Beyond its canonical role, the SRP68/72 heterodimer has a non-canonical nuclear activity, binding histone H4 tails, associating with chromatin, and activating transcription in a manner inhibited by H4R3 methylation (PMID:23048028).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1990 Medium

    Established the primary structure of SRP68 as a basic, glycine-rich protein, providing the molecular starting point but leaving its function undefined since it matched no known protein.

    Evidence cDNA cloning and sequencing of canine SRP68

    PMID:1702390

    Open questions at the time
    • No functional or RNA-binding activity demonstrated
    • No domain architecture defined beyond a glycine-rich region
  2. 1992 High

    Showed that SRP68/72 binds SRP RNA directly, specifically, and at a distinct site from SRP9/14, defining it as an independent RNA-binding module of the particle.

    Evidence Fluorescence anisotropy equilibrium binding assays with fluorescein-labeled SRP RNA

    PMID:1377027

    Open questions at the time
    • Did not resolve which subunit contacts RNA
    • No RNA structural consequence of binding established
  3. 1993 High

    Resolved that SRP68 is the RNA-contacting subunit and the obligatory bridge that recruits SRP72, which cannot bind RNA alone, establishing the assembly hierarchy of the S domain.

    Evidence In vitro reconstitution from purified components with truncation domain mapping

    PMID:8388879

    Open questions at the time
    • Residue-level RNA contacts unmapped
    • Structural basis of the SRP68–SRP72 interface unknown
  4. 1994 High

    Demonstrated in vivo that SRP68 is required for stable SRP assembly and efficient ER protein translocation, linking the biochemical scaffold role to cellular secretion function.

    Evidence Yeast gene disruption with SRP purification, growth, and translocation assays

    PMID:7925282

    Open questions at the time
    • Did not separate assembly defects from translocation defects mechanistically
    • No structural detail of the assembled particle
  5. 2000 Medium

    Revealed an unexpected nucleolar pool of SRP68 in addition to cytoplasmic/ER localization, hinting at partial assembly or non-canonical activity outside the secretory pathway.

    Evidence GFP fusion live-cell imaging and immunofluorescence in rat fibroblasts

    PMID:10618370

    Open questions at the time
    • Functional role of the nucleolar pool not defined
    • Overexpressed GFP fusion may not reflect endogenous distribution
  6. 2008 Medium

    Mapped the SRP RNA helices and residues contacted by SRP68/72 and showed the heterodimer remodels the RNA to protect and create the SRP54-binding site, defining the functional consequence of binding.

    Evidence Chemical/enzymatic RNA probing, SHAPE, systematic helix mutagenesis, and competitive filter binding across assembly intermediates

    PMID:17254600 PMID:18347438 PMID:18564060

    Open questions at the time
    • No atomic-resolution structure of the contacts at this stage
    • Cooperativity mechanism with SRP19 inferred indirectly
  7. 2014 High

    Provided the atomic mechanism of RNA remodeling: SRP68-RBD is a TPR-like module that bends the RNA three-way junction and inserts an arginine-rich motif into the major groove to open the ribosome-contacting 5f loop.

    Evidence X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19

    PMID:24700861

    Open questions at the time
    • SRP68–SRP72 interface not resolved in this structure
    • Did not capture the full-length particle on the ribosome
  8. 2017 High

    Defined the SRP68–SRP72 interface structurally, showing a short SRP68 peptide displaces an SRP72 homodimer to bind its TPR repeats with high affinity, and linked interface-disrupting cancer-associated mutations to loss of ER co-localization.

    Evidence X-ray crystallography of apo-SRP72 and SRP68/72 complex at 1.7 Å with ITC, SEC, mutagenesis, and cellular co-localization

    PMID:16672232 PMID:27899666 PMID:28369529

    Open questions at the time
    • Disease causation by the mutations not established beyond co-localization
    • Full-length heterodimer architecture still incomplete
  9. 2019 High

    Demonstrated with a fully reconstituted human SRP that the heterodimer drives ultrasensitive avidity-based ribosome binding, explaining how SRP engages the ribosome where RNA alone cannot.

    Evidence Recombinant reconstitution of all human SRP components with microscale thermophoresis binding assays

    PMID:30649417

    Open questions at the time
    • Individual ribosome contact sites not mapped at residue level
    • Dynamics during targeting not directly observed
  10. 2024 Medium

    Identified a previously uncharacterized extended dimerization domain of SRP68/72 and proposed it translocates upon SRP receptor docking to detach SRP9/14 and release elongation arrest, extending the mechanistic model to the targeting cycle.

    Evidence Cryo-EM of full-length SRP68/72 with comparative structural analysis

    PMID:38366771

    Open questions at the time
    • Elongation-arrest release model inferred from structural comparison, not directly tested
    • Conformational translocation not captured in a functional intermediate
  11. 2012 Medium

    Uncovered a non-canonical nuclear function in which SRP68/72 binds histone H4 tails and activates transcription, regulated by H4R3 arginine methylation, separating a chromatin role from the cytoplasmic SRP role.

    Evidence Peptide pulldown, in vitro histone tail binding, ChIP, tethered transcription reporter, and PRMT1/PRMT5 regulation assays

    PMID:23048028

    Open questions at the time
    • Target genes regulated in vivo not defined
    • How free heterodimer is partitioned between SRP and chromatin roles unknown
  12. 2017 Medium

    Showed SRP68 mRNA is destabilized by CELF1 and that subunit imbalance impairs cell migration, indicating SRP68 dosage is post-transcriptionally tuned for normal secretory/ECM function.

    Evidence RIP-crosslinking, in vitro CELF1 binding, mRNA half-life in CELF1 knockdown, and SRP68 overexpression wound-healing assay in myoblasts

    PMID:28129347

    Open questions at the time
    • Mechanistic link between imbalance and migration defect not resolved
    • Physiological CELF1–SRP68 regulation in other tissues untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the extended dimerization domain mechanically couples SRP receptor docking to Alu-domain release and elongation-arrest relief, and how the heterodimer is partitioned between its SRP and chromatin functions, remain unresolved.
  • No functional assay directly tests the proposed elongation-arrest release mechanism
  • Regulation distributing SRP68/72 between cytoplasmic and nuclear roles is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0005198 structural molecule activity 2 GO:0042393 histone binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005694 chromosome 1 GO:0005730 nucleolus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-9609507 Protein localization 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
CELF1HISTONE H4SRP RNA (7SL)SRP19SRP72
Complex memberships
SRP68/72 heterodimerSignal recognition particle (SRP)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 SRP68 is a basic protein of 622 amino acids with a glycine-rich region near its amino terminus shared with some RNA-binding proteins; no sequence similarity to any known protein was detected at the time. cDNA cloning and sequencing of canine SRP68 FEBS letters Medium 1702390
1992 SRP68/72 heterodimer binds directly and specifically to SRP RNA (Kd ≤7 nM) by increasing fluorescein anisotropy; binding is independent of and non-cooperative with SRP9/14 binding, indicating the two heterodimers associate randomly and independently with distinct domains of SRP RNA. Fluorescence spectroscopy using fluorescein-labeled SRP RNA, equilibrium binding assays Biochemistry High 1377027
1993 SRP68 alone specifically binds 7S RNA via its NH2-terminal half; SRP72 incorporation into the RNP requires both 7S RNA and SRP68 (SRP72 cannot bind RNA alone); COOH-terminal portions of SRP68 and SRP72 contact each other, so SRP68 acts as a link between 7S RNA and SRP72. In vitro reconstitution of SRP RNP from purified components, domain-mapping with truncation constructs The Journal of cell biology High 8388879
1994 In yeast, Srp68p (SRP68 ortholog) is required for stable expression of yeast SRP: disruption of SRP68 leads to loss of SRP RNA and other SRP proteins, slow growth, and deficient protein translocation across the ER membrane. Gene disruption (knockout), immunoaffinity purification of yeast SRP, cell growth and translocation assays The EMBO journal High 7925282
2000 GFP-SRP68 localizes not only to the cytoplasm and ER (consistent with its affinity for the ER-bound SRP receptor) but also to the nucleolus in transfected rat fibroblasts, suggesting partial SRP assembly or an unidentified activity occurs at the nucleolus. GFP fusion live-cell imaging and immunofluorescence in transfected rat fibroblasts Proceedings of the National Academy of Sciences of the United States of America Medium 10618370
2006 The RNA-binding domain of SRP68 spans residues 52–252; a ~94-residue C-terminal region mediates binding to SRP72; the SRP68–SRP72 interaction is salt-stable and engages ~150 N-terminal residues of SRP72 within its predicted TPR-like region. Recombinant protein expression and purification, proteolytic fragment binding assays (pulldown/filter binding) Protein science Medium 16672232
2006 SRP68/72 binding to 7SL RNA brings the lower parts of helices 6 and 8 closer together, protects the SRP54 binding site (helix 8 asymmetric loop) from chemical modification, and—together with SRP19—rearranges the RNA into an SRP54-binding-competent state. Chemical and enzymatic probing (ethylation interference, hydroxyl radical footprinting, DMS modification, RNase cleavage) of all S-domain assembly intermediates Journal of molecular biology High 17254600
2007 SRP68/72 contacts SRP RNA primarily through residues in helices 5 (positions 222–231) and helix 8 (positions 176–191 and 202–214); SRP72 alone contacts only the 5ef region of helix 5 (residues 120–128) and does not require helices 6 or 8. Systematic mutagenesis of 18 SRP RNA helix positions combined with competitive double-filter binding assay with purified SRP68/72 and a SRP72 fragment RNA biology Medium 18347438
2008 SRP19 and SRP68/72 both bind helices 6 and 8 of SRP RNA but on opposite faces and at opposite ends; SRP72 binds largely via non-electrostatic interactions and enhances SRP68 affinity; the two proteins bind with moderate anti-cooperativity, arising from stabilization of distinct RNA conformations. Quantitative binding assays (filter binding), SHAPE RNA probing, analysis of cooperativity between SRP19 and SRP68/72 The Biochemical journal Medium 18564060
2012 SRP68/72 heterodimer (but not intact SRP) binds histone H4 tail peptides in vitro; H4R3 methylation (by PRMT1 or PRMT5) inhibits this binding; SRP68 and SRP72 associate with chromatin in vivo and activate transcription when tethered to a reporter, revealing a non-canonical chromatin/transcriptional regulatory function. Peptide pulldown/proteomics, in vitro histone tail binding assay, ChIP, tethered transcription reporter assay, PRMT1/PRMT5 regulation The Journal of biological chemistry Medium 23048028
2014 Crystal structures of the SRP68 RNA-binding domain (SRP68-RBD) alone and in complex with SRP RNA and SRP19 reveal that SRP68-RBD is a tetratricopeptide-like module that binds a RNA three-way junction, bends the RNA, and inserts an α-helical arginine-rich motif (ARM) into the RNA major groove, thereby opening the conserved 5f RNA loop (which contacts ribosomal RNA in ribosome-bound SRP). X-ray crystallography of SRP68-RBD alone and in ternary complex with SRP RNA and SRP19 Science High 24700861
2016 Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD and of SRP72-RBD bound to the full S domain show: SRP72-PBD is a TPR repeat that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along 5e/5f RNA loops; a conserved tryptophan inserts into the 5e loop forming a novel K⁺-stabilized RNA kink-turn; SRP72-RBD remodels the 5f loop involved in ribosome binding. Cryo-EM docking reveals multiple SRP68/72–ribosome contact sites. X-ray crystallography of SRP68-PBD/SRP72-PBD complex and SRP72-RBD/S-domain complex; cryo-EM docking Nucleic acids research High 27899666
2017 Crystal structures of human apo-SRP72 and the SRP68/72 complex (1.7 Å) show SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 dimerizes in solution but the homodimer dissociates to accommodate SRP68; a 23-residue hydrophobic extended peptide of SRP68 is sufficient for tight binding to SRP72. Cancer-associated mutations that disrupt SRP68–SRP72 interaction also abolish their co-localization with ER in mammalian cells. X-ray crystallography (apo-SRP72 and SRP68/72 complex), biophysical analyses (SEC, ITC), mutagenesis, co-localization in mammalian cells Journal of molecular cell biology High 28369529
2017 CELF1 directly binds the SRP68 mRNA and destabilizes it; overexpression of SRP68 alone (causing SRP subunit imbalance) impairs cell migration/wound healing, indicating that balanced SRP68 levels are required for normal secretion and extracellular matrix function in myoblasts. RIP-crosslinking, in vitro CELF1 binding assay, mRNA half-life measurement in CELF1 KD cells, SRP68 overexpression with wound-healing assay PloS one Medium 28129347
2019 Reconstituted human SRP68/72 heterodimer shows ultrasensitive (avidity-based) binding to the ribosome via multiple contact sites dominated by the C-terminus of SRP72; SRP RNA alone does not bind the ribosome; full SRP binds ribosomes with nanomolar affinity through a two-step mechanism involving SRP54. Large-scale recombinant reconstitution of all human SRP components; microscale thermophoresis binding assays for individual components and assembly intermediates Nucleic acids research High 30649417
2024 Cryo-EM of full-length SRP68/72 reveals an extended dimerization domain beyond the previously characterized domains; SRP68 and SRP72 depend on each other for stability. The newly identified dimerization domain is both a protein- and RNA-binding domain. Comparative structural analysis suggests this domain undergoes dramatic translocation upon SRP docking onto the SRP receptor and positions near the Alu domain, indicating it may release elongation arrest by binding and detaching SRP9/14 from the ribosomal surface. Cryo-EM structure of full-length SRP68/72; comparative structural analysis with existing models Nucleic acids research Medium 38366771

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Signal recognition particle components in the nucleolus. Proceedings of the National Academy of Sciences of the United States of America 167 10618370
1994 Subunits of the Saccharomyces cerevisiae signal recognition particle required for its functional expression. The EMBO journal 104 7925282
2003 SRPDB: Signal Recognition Particle Database. Nucleic acids research 95 12520023
2006 The tmRDB and SRPDB resources. Nucleic acids research 88 16381838
2002 Structure of the SRP19 RNA complex and implications for signal recognition particle assembly. Nature 84 12050674
1994 Molecular evolution of SRP cycle components: functional implications. Nucleic acids research 74 7518075
2011 Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type. BMC cancer 54 21812966
2014 Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP. Cell death & disease 49 24434517
2001 SRPDB (Signal Recognition Particle Database). Nucleic acids research 47 11125080
1997 The crystal structure of the signal recognition particle Alu RNA binding heterodimer, SRP9/14. The EMBO journal 46 9233785
1993 Assembly of the 68- and 72-kD proteins of signal recognition particle with 7S RNA. The Journal of cell biology 43 8388879
2014 SRP RNA remodeling by SRP68 explains its role in protein translocation. Science (New York, N.Y.) 38 24700861
2005 The Trypanosoma brucei signal recognition particle lacks the Alu-domain-binding proteins: purification and functional analysis of its binding proteins by RNAi. Journal of cell science 35 16179612
1998 The Signal Recognition Particle Database (SRPDB). Nucleic acids research 35 9399828
2006 Protein-induced conformational changes of RNA during the assembly of human signal recognition particle. Journal of molecular biology 34 17254600
1992 Fluorescence-detected assembly of the signal recognition particle: binding of the two SRP protein heterodimers to SRP RNA is noncooperative. Biochemistry 31 1377027
2008 Role of protein translocation pathways across the endoplasmic reticulum in Trypanosoma brucei. The Journal of biological chemistry 30 18768469
2015 Differentially expressed genes in metastatic advanced Egyptian bladder cancer. Asian Pacific journal of cancer prevention : APJCP 29 25921176
2019 Reconstitution of the human SRP system and quantitative and systematic analysis of its ribosome interactions. Nucleic acids research 28 30649417
2016 Structures of human SRP72 complexes provide insights into SRP RNA remodeling and ribosome interaction. Nucleic acids research 28 27899666
1990 The 68 kDa protein of signal recognition particle contains a glycine-rich region also found in certain RNA-binding proteins. FEBS letters 26 1702390
2021 Noncanonical Functions and Cellular Dynamics of the Mammalian Signal Recognition Particle Components. Frontiers in molecular biosciences 21 34113652
2020 Transcriptome-based selection and validation of optimal house-keeping genes for skin research in goats (Capra hircus). BMC genomics 19 32682387
2017 Human apo-SRP72 and SRP68/72 complex structures reveal the molecular basis of protein translocation. Journal of molecular cell biology 17 28369529
2012 A novel histone H4 arginine 3 methylation-sensitive histone H4 binding activity and transcriptional regulatory function for signal recognition particle subunits SRP68 and SRP72. The Journal of biological chemistry 17 23048028
2006 Protein SRP68 of human signal recognition particle: identification of the RNA and SRP72 binding domains. Protein science : a publication of the Protein Society 17 16672232
1996 The Signal Recognition Particle Database (SRPDB). Nucleic acids research 17 8594607
2007 Down-regulation of the trypanosomatid signal recognition particle affects the biogenesis of polytopic membrane proteins but not of signal peptide-containing proteins. Eukaryotic cell 16 17715370
1997 The Signal Recognition Particle Database (SRPDB). Nucleic acids research 12 9016514
2017 The CELF1 RNA-Binding Protein Regulates Decay of Signal Recognition Particle mRNAs and Limits Secretion in Mouse Myoblasts. PloS one 11 28129347
2007 Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA. RNA biology 9 18347438
1994 The signal recognition particle database (SRPDB). Nucleic acids research 6 7524020
2008 Anti-cooperative assembly of the SRP19 and SRP68/72 components of the signal recognition particle. The Biochemical journal 5 18564060
2021 Mycoplasma genitalium Protein of Adhesion Promotes the Early Proliferation of Human Urothelial Cells by Interacting with RPL35. Pathogens (Basel, Switzerland) 4 34832605
2024 Cryo-EM structure of SRP68/72 reveals an extended dimerization domain with RNA-binding activity. Nucleic acids research 2 38366771

Missed literature

Know a paper Affinage missed for SRP68? Flag it for the maintainers and the community.

No submissions yet.