SRPRA

SRPRA (SRPRα) is the GTPase subunit of the signal recognition particle (SRP) receptor that governs cotranslational targeting of nascent secretory and membrane proteins to the endoplasmic reticulum (PMID:9182758). SRPRα and SRP54 begin nucleotide-free and cooperatively bind GTP upon SRP–SR docking to stabilize the targeting complex—with SRPRα playing the dominant stabilization role—enabling handoff of the signal sequence to Sec61α, after which GTP hydrolysis by both subunits drives complex dissociation (PMID:9182758). These activities reside in the NG domain, which mediates SRP54 interaction, RNA binding, and GTP binding/hydrolysis (PMID:35640773). In vivo, loss of SRPRA disrupts SRP-dependent protein processing, intracellular trafficking, and proteome homeostasis, and biallelic SRPRA defects cause severe congenital neutropenia by blocking neutrophil granulocyte differentiation in human iPSC and zebrafish models (PMID:36223592). SRPRA expression promotes keratinocyte proliferation through cell-cycle progression and is directly repressed by miR-330-5p (PMID:27768721).

1. 1997 High

   Established how the SRP receptor enforces fidelity in protein targeting by defining the coupled SRPRα–SRP54 GTPase cycle from empty state through GTP-stabilized docking to hydrolysis-driven release.

   Evidence In vitro GTPase assays and reconstituted ribosome-nascent chain targeting with defined nucleotide-binding states

   PMID:9182758

   Open questions at the time

   • Structural basis of cooperative GTP binding not resolved here
   • Kinetics of signal-sequence handoff to Sec61α not quantified
   • Contribution of individual domains to each step not dissected
2. 2016 Medium

   Connected SRPRA dosage to a tissue-level proliferative phenotype, showing it drives keratinocyte cell-cycle progression and is a direct miR-330-5p target.

   Evidence SRPRA knockdown with cell cycle analysis and luciferase reporter validation of miR-330-5p binding in mouse keratinocytes

   PMID:27768721

   Open questions at the time

   • No mechanistic link between SRP targeting function and cell-cycle control
   • Single lab with no pathway placement beyond cell cycle
   • Whether the proliferation effect reflects general secretory load is unknown
3. 2022 Medium

   Assigned SRP54 interaction, RNA binding, and GTP binding/hydrolysis to the human SRPRα NG domain and enabled full-length NG structural study by including the previously omitted N-terminal helix.

   Evidence Recombinant expression/purification with isotopic labeling for NMR and domain boundary mapping

   PMID:35640773

   Open questions at the time

   • Functional role of the N-terminal helix in protein–protein interactions not determined
   • Single lab, single method
   • No structure reported in this work
4. 2023 High

   Demonstrated that SRPRA-dependent cotranslational targeting is critically required for neutrophil differentiation, defining a Mendelian disease link to severe congenital neutropenia.

   Evidence Patient genetics, iPSC-to-neutrophil differentiation, zebrafish knockout, quantitative proteomics, and heterologous protein-expression validation

   PMID:36223592

   Open questions at the time

   • Why neutrophil lineage is selectively vulnerable not mechanistically explained
   • Specific client proteins driving the differentiation block only partially defined
   • Genotype-phenotype relationship across mutations not established

• How the general SRP targeting defect produces cell-type-specific outcomes (neutrophil block versus keratinocyte proliferation) and the structural basis of the N-terminal helix function remain unresolved.
• No unifying model linking SRP function to lineage-specific phenotypes
• N-terminal helix interaction partners unknown
• No high-resolution structure of full-length human SRPRα in the corpus