Affinage

SRP72

Signal recognition particle subunit SRP72 · UniProt O76094

Length
671 aa
Mass
74.6 kDa
Annotated
2026-06-10
14 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SRP72 is the largest subunit of the signal recognition particle (SRP), where it bridges SRP RNA and the SRP68 partner protein to support co-translational targeting of secretory proteins to the ER (PMID:27899666, PMID:15588816). Its C-terminal RNA-binding region (minimally residues 545–585) crawls along the 5e- and 5f-loops of the large SRP RNA domain: a lysine-rich cluster and the conserved PDPXRWLPXXER motif—with W577 inserting into the 5e-loop—stabilize a potassium-dependent K-turn anchored by the conserved adenosine A240, while remodeling the 5f-loop implicated in ribosome binding (PMID:27899666, PMID:18441046, PMID:21073748). Binding specificity is restricted to the 5ef region of SRP RNA, as the isolated SRP72 RNA-binding fragment is sensitive only to helix-5 mutations (PMID:18347438). The N-terminal domain comprises atypical tetratricopeptide (TPR) repeats forming a superhelical groove that captures an extended linear peptide of SRP68; heterodimer formation requires dissociation of an apo-SRP72 homodimer and a conformational change in a C-terminal cap (PMID:27899666, PMID:28369529, PMID:16672232). Beyond the SRP, the SRP68/72 heterodimer—but not intact SRP—binds the histone H4 tail, associates with chromatin under control of PRMT1/PRMT5-mediated H4R3 methylation, and activates transcription when tethered to a reporter, defining a distinct nuclear regulatory function (PMID:23048028). Heterozygous SRP72 mutations cause familial aplastic anemia/myelodysplastic syndrome, with disease variants disrupting SRP68 binding, ER co-localization, and SRP RNA association (PMID:28369529, PMID:22541560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2005 High

    Established that SRP72 is a bifunctional protein with a discrete C-terminal RNA-binding module and an N-terminal TPR array, answering where in the protein RNA contact occurs.

    Evidence Recombinant fragment expression, limited proteolysis, filter-binding and sucrose-gradient assays with SRP RNA mutants

    PMID:15588816

    Open questions at the time
    • Atomic-resolution geometry of RNA contact not resolved
    • TPR partner not yet identified biochemically
  2. 2006 Medium

    Defined the SRP68–SRP72 interaction interface, showing the N-terminal TPR-like motifs of SRP72 form the SRP68 docking surface.

    Evidence Recombinant binding/pulldown assays with defined domain fragments of SRP68 and SRP72

    PMID:16672232

    Open questions at the time
    • No structure of the complex
    • Stoichiometry and conformational requirements unknown
  3. 2007 Medium

    Distinguished SRP72-alone RNA contacts from those of the SRP68/72 heterodimer, mapping SRP72 specifically to the 5ef region of the large SRP RNA domain.

    Evidence Competitive double-filter binding with 18 SRP RNA helix mutants and purified proteins

    PMID:18347438

    Open questions at the time
    • Single-lab biochemistry
    • Functional consequence on targeting not measured
  4. 2008 Medium

    Pinpointed conserved adenosine A240 in the 5e motif as essential for SRP72 binding, narrowing the recognition determinant to a single helical section.

    Evidence Chimeric human/archaeal SRP RNA constructs, site-directed mutagenesis, filter-binding and competition assays

    PMID:18441046

    Open questions at the time
    • Structural basis of A240 recognition inferred, not visualized
    • Single lab
  5. 2010 Medium

    Resolved the minimal RNA-binding peptide and the sequence elements (lysine cluster, PDPXRWLPXXER motif, W577) needed for SRP RNA engagement, and modeled the 5e kink-turn.

    Evidence Site-directed mutagenesis with binding readout, native PAGE, molecular modeling, chymotryptic mapping

    PMID:21073748

    Open questions at the time
    • Kink-turn model partly computational
    • K+ dependence not yet demonstrated
  6. 2012 Medium

    Uncovered a moonlighting nuclear role: the SRP68/72 heterodimer binds the histone H4 tail, occupies chromatin under PRMT control, and can activate transcription, separating this function from the SRP.

    Evidence Histone tail peptide pulldown, Co-IP, chromatin association, transcriptional reporter, genome-wide occupancy

    PMID:23048028

    Open questions at the time
    • Direct transcriptional targets not defined
    • Mechanism of nuclear versus cytoplasmic partitioning unknown
  7. 2012 Medium

    Linked SRP72 to human disease, showing heterozygous mutations in familial aplastic anemia/MDS mislocalize the protein and impair SRP RNA association.

    Evidence Mutant construct transfection (localization) and Co-IP of epitope-tagged SRP72 in mammalian cells

    PMID:22541560

    Open questions at the time
    • Mechanistic path from SRP defect to hematopoietic failure unresolved
    • Limited mechanistic depth, single lab
  8. 2016 High

    Provided the structural mechanism: SRP72-TPR binds an extended SRP68 motif, and the flexible SRP72-RBD crawls along the 5e/5f loops with a tryptophan forming a K+-stabilized turn while remodeling the ribosome-binding 5f-loop.

    Evidence X-ray crystallography of SRP68-PBD/SRP72-PBD and SRP72-RBD/S domain, cryo-EM docking onto ribosome maps

    PMID:27899666

    Open questions at the time
    • Dynamics of RBD crawling during the targeting cycle not captured
    • Ribosome contacts inferred from docking
  9. 2017 High

    Showed the conformational logic of heterodimer assembly—apo-SRP72 is a homodimer whose dissociation and C-terminal cap rearrangement enable SRP68 capture—and connected cancer-associated residues to interface disruption.

    Evidence Crystal structures of apo-SRP72 and SRP68/72 complex, biophysics, mutagenesis, cell co-localization

    PMID:28369529

    Open questions at the time
    • Trigger for homodimer-to-heterodimer transition in cells unknown
    • Functional role of homodimer state undefined
  10. 2019 Medium

    Connected SRP72 gene dosage to secretory output in vivo: heterozygous Srp72 loss down-regulates genes encoding secreted factors in hematopoietic cells.

    Evidence Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis

    PMID:31254415

    Open questions at the time
    • No overt hematological phenotype, leaving disease mechanism incomplete
    • Whether transcriptional changes are direct (chromatin role) or indirect (ER targeting) not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SRP72's cytoplasmic SRP function and its nuclear chromatin/transcriptional function are coordinated, and how either is perturbed to cause bone marrow failure, remains unresolved.
  • No mechanism connecting SRP RNA binding defects to hematopoietic disease
  • Regulation of SRP68/72 nuclear partitioning unknown
  • Phosphorylation sites and functional consequence of MAPK-dependent modification undefined

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:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
PRMT1PRMT5SRP68
Complex memberships
SRP68/72 heterodimersignal recognition particle (SRP)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Crystal structures of the SRP68 protein-binding domain (PBD) in complex with SRP72-PBD, and of the SRP72-RNA-binding domain (RBD) bound to the SRP S domain, revealed that SRP72-PBD contains a tetratricopeptide repeat (TPR) that binds an extended linear motif of SRP68 with high affinity; SRP72-RBD is a flexible peptide that crawls along the 5e- and 5f-loops of SRP RNA, with a conserved tryptophan inserting into the 5e-loop to form a novel K+-turn stabilized by a potassium ion; SRP72-RBD also remodels the 5f-loop involved in ribosome binding. Docking of the S domain into cryo-EM density maps identified multiple contact sites between SRP68/72 and the ribosome. X-ray crystallography, cryo-EM docking, structural analysis Nucleic acids research High 27899666
2017 Crystal structures of human apo-SRP72 and the SRP68/72 complex showed that the SRP68-binding domain of SRP72 contains four atypical TPR repeats and a flexible C-terminal cap; apo-SRP72 exists as a homodimer in solution, and homodimer dissociation plus a pronounced conformational change in the C-terminal cap are required for SRP68/72 heterodimer formation. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 via an unusually hydrophobic extended surface. Mutagenesis of cancer-associated residues disrupted SRP68-SRP72 interaction and their co-localization with ER. X-ray crystallography (2.91 Å apo-SRP72; 1.7 Å complex), biophysical assays, site-directed mutagenesis, co-localization in mammalian cells Journal of molecular cell biology High 28369529
2005 A 63-amino-acid region near the C-terminus of SRP72 binds SRP RNA with high affinity; within this region a 56-residue RNA-binding domain contains the conserved consensus PDPXRWLPXXER. Chymotrypsin treatment of this fragment abolishes RNA-binding activity. SRP72 binds specifically to the moderately conserved portion of SRP RNA helix 5, as shown by sucrose gradient centrifugation and filter-binding assays with mutant SRP RNAs. The NH2-terminal region contains nine TPR-like repeats predicted to interact with SRP or ribosomal proteins. Recombinant protein expression, limited proteolysis, filter-binding assay, sucrose gradient centrifugation, SRP RNA mutagenesis Journal of molecular biology High 15588816
2006 SRP68 binds recombinant SRP72 and SRP RNA in vitro. The RNA-binding domain of SRP68 spans residues 52–252, while a 94-amino-acid C-terminal region of SRP68 mediates binding to SRP72. The SRP68-SRP72 interaction is stable at elevated salt concentrations and engages approximately 150 N-terminal residues of SRP72, which lie within a predicted tandem array of four TPR-like motifs forming a superhelical groove. Recombinant protein expression in E. coli, pulldown/binding assays, proteolytic fragment mapping Protein science Medium 16672232
2007 Systematic mutagenesis of 18 positions in SRP RNA helices 5, 6, and 8 showed that binding of the SRP68/72 heterodimer is impaired by mutations throughout the large SRP RNA domain, with strongest effects in helix 5 (residues 222–231) and helix 8 (residues 176–191 and 202–214). In contrast, a 7.4-kDa RNA-binding fragment of SRP72 alone is diminished primarily by mutations in helix 5 (residues 120–128) and is unaffected by deletion of helices 6 and 8, demonstrating that SRP72 contacts only the 5ef region of the large SRP RNA domain. Competitive double-filter binding assay with purified proteins and 18 mutant SRP RNAs RNA biology Medium 18347438
2008 The 5e motif of human SRP RNA contains the conserved adenosine A240 that is essential for SRP72 binding; A240G or A240C substitutions dramatically reduce binding of the SRP72 C-terminal fragment (72c'), and full-length SRP72 cannot form a complex with A240G-mutant SRP RNA. Chimera experiments with human and archaeal SRP RNAs confirmed that the 5e helical section alone contains the SRP72 binding site and no other SRP RNA regions are required. Chimeric SRP RNA construction, site-directed mutagenesis, filter-binding assay, competitive binding with RNA fragments RNA Medium 18441046
2010 The minimal SRP72 RNA-binding region spans residues 545–585 and requires both a lysine-rich cluster (K552–K561) and the conserved PDPXRWLPXXER motif (W577 in particular). Site-directed mutagenesis of both regions impairs SRP RNA complex formation. Molecular modeling and native gel electrophoresis showed that the 5e motif forms a kink-turn, with conserved A240 likely protruding into a groove of the SRP72 RNA-binding domain. Site-directed mutagenesis, native PAGE, molecular modeling, chymotryptic digestion mapping BMC molecular biology Medium 21073748
2012 SRP68/72 heterodimers (but not the intact SRP complex) bind the histone H4 tail peptide in vitro, and this binding is inhibited by H4R3 methylation. SRP68 and SRP72 associate with chromatin in vivo, regulated by PRMT5 and PRMT1. When tethered to a reporter gene via a heterologous DNA-binding domain, both SRP68 and SRP72 activate transcription, identifying a chromatin/transcriptional regulatory function for the SRP68/72 heterodimer distinct from its SRP role. Proteomic pulldown with histone H4 tail peptides, Co-IP, chromatin association assay, transcriptional reporter assay, genome-wide occupancy analysis The Journal of biological chemistry Medium 23048028
2012 Heterozygous SRP72 mutations in familial aplastic anemia/MDS patients cause mislocalization of the SRP72 protein within mammalian cells (transfection experiments), and one SRP72 variant fails to fully associate with the SRP RNA component as shown by co-immunoprecipitation of epitope-tagged SRP72. Transfection of mutant constructs in mammalian cells (localization), co-immunoprecipitation with epitope-tagged SRP72 American journal of human genetics Medium 22541560
2010 IL-1β stimulation of Jurkat cells causes up-regulation of SRP72 protein expression and SRP72 phosphorylation; pharmacological inhibition of ERK1/2 or p38α/β MAPK pathways suppresses both the IL-1β-induced expression and phosphorylation of SRP72, placing SRP72 phosphorylation downstream of MAPK signaling. Immunoprecipitation, immunoprecipitation-Western blotting, real-time PCR, MAPK inhibitor treatment in Jurkat cells The Journal of biological chemistry Low 20729213
2019 Heterozygous loss of Srp72 in mice leads to transcriptional down-regulation of genes encoding secreted factors (cytokines and receptors) in hematopoietic cells, consistent with SRP72's role in targeting secretory proteins to the ER; however, no major hematological disorder phenotype was observed. Srp72 null mouse model, flow cytometry, bone marrow transplantation, gene expression analysis European journal of haematology Medium 31254415

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. American journal of human genetics 87 22541560
2016 Structures of human SRP72 complexes provide insights into SRP RNA remodeling and ribosome interaction. Nucleic acids research 28 27899666
2010 Inhibitors of MAPK pathway ERK1/2 or p38 prevent the IL-1{beta}-induced up-regulation of SRP72 autoantigen in Jurkat cells. The Journal of biological chemistry 21 20729213
2005 Identification of an RNA-binding domain in human SRP72. Journal of molecular biology 21 15588816
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
2019 Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes. European journal of haematology 9 31254415
2008 The 5e motif of eukaryotic signal recognition particle RNA contains a conserved adenosine for the binding of SRP72. RNA (New York, N.Y.) 9 18441046
2007 Identification of the RNA binding regions of SRP68/72 and SRP72 by systematic mutagenesis of human SRP RNA. RNA biology 9 18347438
2010 Identification of amino acid residues in protein SRP72 required for binding to a kinked 5e motif of the human signal recognition particle RNA. BMC molecular biology 8 21073748
2023 A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications. Journal of clinical medicine 2 37176611
2026 A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature. Molecular genetics & genomic medicine 1 41472573
2025 A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report. Cureus 0 40922878

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