GO:0031207 Sec62/Sec63 complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031207 (Sec62/Sec63 complex) is a protein complex that mediates the posttranslational targeting of proteins to the endoplasmic reticulum (ER).
• In yeast, the complex is a tetramer of Sec62p, Sec63p, Sec71p and Sec72p; in mammals, Sec62 and Sec63 associate with the Sec61 channel.
• Sec63 contains a J-domain that stimulates the ER Hsp70 chaperone BiP, while Sec62 contributes to channel gating and signal-peptide recognition.
• The complex is essential for ER protein import, and its subunits are implicated in cancer, viral infection and developmental processes.
• Loss-of-function studies in model organisms show that Sec62/Sec63 genes are required for survival and tissue development.
• CRISPR-based knockout, point mutation, knock-in and overexpression models enable precise dissection of Sec62/Sec63 complex function in health and disease.
Description
The Sec62/Sec63 complex (GO:0031207) is a conserved protein complex that functions in the posttranslational targeting of proteins to the endoplasmic reticulum (ER). It is defined in the Gene Ontology as a protein complex involved in the posttranslational targeting of proteins to the ER; in yeast, it is a tetrameric complex consisting of Sec62p, Sec63p, Sec71p and Sec72p. This complex is a key component of the ER protein translocation machinery and is essential for the biogenesis of secretory and membrane proteins. The Sec62/Sec63 complex has attracted attention because its subunits are involved in human diseases, including cancer, and because it regulates the ER stress response and calcium homeostasis. Understanding its structure, assembly and regulation is therefore important for both basic cell biology and translational research.
Sec62/Sec63 complex At A Glance
| GO ID | GO:0031207 |
|---|---|
| GO term | Sec62/Sec63 complex |
| Ontology | cellular_component |
| Synonym | ER protein translocation subcomplex; Sec62/63 complex |
| Major function | Posttranslational targeting of proteins to the ER and regulation of the Sec61 channel |
| Yeast composition | Tetramer of Sec62p, Sec63p, Sec71p and Sec72p |
| Mammalian composition | Sec62 and Sec63 associated with Sec61 |
| Key interacting chaperone | BiP (Hsp70) via the J-domain of Sec63 |
| Disease relevance | Cancer, viral infection, ER stress-related disorders |
What Is GO:0031207?
GO:0031207 (Sec62/Sec63 complex) is a cellular component ontology term describing a protein complex that mediates the posttranslational targeting of proteins to the endoplasmic reticulum. In yeast, the complex is a tetramer composed of Sec62p, Sec63p, Sec71p and Sec72p. In mammals, Sec62 and Sec63 are associated with the Sec61 channel and function in protein import into the ER.
Why Is Sec62/Sec63 complex Important in Cell Biology?
The Sec62/Sec63 complex is essential for ER protein import, a process required for the biogenesis of approximately one-third of the proteome. Its subunits are involved in human diseases, particularly cancer, where Sec62 and Sec63 expression is altered and correlates with patient prognosis. The complex also regulates the Sec61 channel, influencing ER calcium homeostasis and stress responses. Therefore, understanding the Sec62/Sec63 complex provides insights into fundamental cell biology and offers potential targets for therapeutic intervention.
• Essential for posttranslational ER protein import and secretory pathway function.
• Regulates the Sec61 protein-conducting channel via Sec62 and Sec63.
• Sec63 J-domain stimulates BiP ATPase activity, driving polypeptide translocation.
• Sec62 contributes to signal peptide recognition and substrate specificity.
• Altered expression of Sec62 and Sec63 is observed in multiple cancers.
• Sec62/Sec63 genes are required for survival and development in insects.
• The complex is a target for viral pathogens that hijack ER translocation.
• Mutations in Sec63 are linked to autosomal dominant polycystic liver disease (ADPLD).
• Sec62/Sec63 dysfunction is associated with ER stress and neurodegenerative conditions.
• CRISPR screens can identify synthetic lethal interactions with Sec62/Sec63 loss.
Sec62/Sec63 complex: Biological Process, Cellular Component and Molecular Function
Posttranslational Targeting to the ER
In simple terms: Proteins that are fully made in the cytosol are delivered to the ER by the Sec62/Sec63 complex.
The Sec62/Sec63 complex mediates the posttranslational targeting of proteins to the ER. In this pathway, fully synthesized polypeptides are recognized by Sec62 and delivered to the Sec61 channel, with Sec63 facilitating translocation. This route is particularly important for small proteins that are not efficiently targeted co-translationally.
Gating of the Sec61 Channel
In simple terms: Sec62 and Sec63 act like gatekeepers that open and close the protein tunnel in the ER membrane.
Sec62 and Sec63 regulate the opening and closing of the Sec61 protein-conducting channel. Structural and computational studies show that Sec63 binding induces conformational changes in Sec61 that prime the channel for translocation, while Sec62 contributes to channel gating. This stepwise gating ensures efficient protein import and prevents inappropriate channel opening.
Stimulation of BiP by the Sec63 J-Domain
In simple terms: Sec63 acts as a co-chaperone that activates BiP, a molecular motor that pulls proteins into the ER.
The J-domain of Sec63 stimulates the ATPase activity of the ER Hsp70 chaperone BiP. This drives the ratchet mechanism that pulls polypeptides into the ER lumen. This function is conserved from yeast to humans and is essential for posttranslational translocation.
Substrate Recognition and Signal Peptide Specificity
In simple terms: Sec62 recognizes features in the signal peptide of cargo proteins, determining which proteins use this pathway.
Human Sec62/Sec63-dependent ER import requires specific signal peptide features. Proteomic and biochemical studies identified signal peptide characteristics that determine substrate specificity for the Sec62/Sec63 pathway. This ensures that appropriate proteins are targeted posttranslationally while others use co-translational routes.
Assembly and Stoichiometry of the Complex
In simple terms: The complex is built from several subunits that come together in a defined arrangement.
In yeast, the Sec62/Sec63 complex is a tetramer of Sec62p, Sec63p, Sec71p and Sec72p. In mammals, Sec62 and Sec63 are associated with the Sec61 complex. The assembly of these subunits is coordinated with the ER membrane and requires specific protein-protein interactions.
Key Genes Involved in GO:0031207 Sec62/Sec63 complex
The following genes and proteins are core components or regulators of the Sec62/Sec63 complex (GO:0031207).
| Gene | Major Role | Research Relevance |
|---|---|---|
| SEC62 | Subunit of the Sec62/Sec63 complex; involved in posttranslational ER import and signal peptide recognition | Cancer biomarker; target for knockout and overexpression studies |
| SEC63 | Subunit with J-domain that stimulates BiP; regulates Sec61 gating | Mutations in ADPLD; cancer; knockout models |
| SEC61A1 | Core channel of the ER translocon; interacts with Sec62/Sec63 | Channel gating studies; knockout is lethal |
| SEC71 | Yeast-specific subunit of the tetrameric Sec62/Sec63 complex | Yeast genetics; assembly studies |
| SEC72 | Yeast-specific subunit of the tetrameric Sec62/Sec63 complex | Yeast genetics; assembly studies |
| HSPA5 (BiP) | ER Hsp70 chaperone stimulated by Sec63 J-domain | Chaperone mechanism; ER stress studies |
| SEC61B | Accessory subunit of Sec61 complex | Interactome studies |
| SEC61G | Accessory subunit of Sec61 complex | Cancer; interactome studies |
| GET1 | ER membrane protein involved in tail-anchored protein insertion | Parallel pathway studies |
| GET2 | ER membrane protein involved in tail-anchored protein insertion | Parallel pathway studies |
| GET3 | Cytosolic ATPase for tail-anchored protein targeting | Parallel pathway studies |
| SSR1 | TRAP complex subunit; co-translational translocation | Comparative studies |
| SSR2 | TRAP complex subunit; co-translational translocation | Comparative studies |
| SSR3 | TRAP complex subunit; co-translational translocation | Comparative studies |
| SSR4 | TRAP complex subunit; co-translational translocation | Comparative studies |
| CALR | ER chaperone; calcium homeostasis | ER stress studies |
| CANX | ER chaperone; calcium homeostasis | ER stress studies |
| ATF6 | ER stress sensor; UPR | Cross-talk with Sec62/Sec63 |
How Is Sec62/Sec63 complex Regulated?
The Sec62/Sec63 complex is regulated at multiple levels. Its expression is induced by ER stress as part of the unfolded protein response (UPR). Sec62 and Sec63 protein levels are also controlled by proteasomal degradation and autophagy. In cancer, Sec62 is overexpressed and its expression correlates with tumor progression. The J-domain of Sec63 is regulated by BiP binding and nucleotide exchange factors. Additionally, posttranslational modifications such as phosphorylation may modulate complex assembly and function.
Sec62/Sec63 complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SEC62 | Cancer (lung, prostate, etc.) | Knockout and overexpression in cancer cell lines; xenograft models |
| SEC63 | Autosomal dominant polycystic liver disease (ADPLD) | Knock-in of patient mutations in cell lines; liver organoids |
| SEC61A1 | ER protein import defects; cancer | Point mutations in Sec61A1; knockout is lethal |
| HSPA5 (BiP) | ER stress-related diseases | Knockout and overexpression; ER stress inducers |
| SEC62/SEC63 | Viral infection | CRISPR knockout in viral permissive cells; viral replication assays |
Cancer
Sec62 and Sec63 are differentially expressed in various cancers. Sec62 overexpression is associated with poor prognosis in lung, prostate and other cancers, and promotes cell migration and invasion. Sec63 mutations are linked to autosomal dominant polycystic liver disease (ADPLD) and may also play a role in tumorigenesis. Targeting the Sec62/Sec63 complex is being explored as a therapeutic strategy.
Autosomal Dominant Polycystic Liver Disease (ADPLD)
Mutations in SEC63 cause ADPLD, a genetic disorder characterized by multiple fluid-filled cysts in the liver. SEC63 mutations impair ER protein import and lead to cyst formation through mechanisms involving polycystin-1 maturation.
Viral Infection
Many viruses hijack the ER translocation machinery for the synthesis of viral glycoproteins. Sec62/Sec63 subunits are required for efficient replication of certain viruses, making them potential antiviral targets.
Neurodegeneration
ER protein misfolding is a hallmark of neurodegenerative diseases. Dysfunction of the Sec62/Sec63 complex may exacerbate ER stress and contribute to neuronal death, although direct evidence is still emerging.
From Sec62/Sec63 complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is SEC62 essential for cell viability? | CRISPR knockout in human cell lines (e.g., HeLa, HEK293) |
| How do SEC63 mutations affect ER import? | Point mutation knock-in of ADPLD-associated variants |
| Does Sec62 overexpression promote migration? | Overexpression in cancer cell lines; wound healing assays |
| What is the interactome of Sec62/Sec63? | Tagged knock-in (e.g., GFP, BioID) followed by mass spectrometry |
| Can Sec62/Sec63 loss be rescued by Sec61? | Knockout plus rescue with wild-type or mutant Sec61 |
| What genes are synthetic lethal with SEC62 loss? | CRISPR library screening in SEC62-knockout background |
How to Study the Sec62/Sec63 complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function phenotype | Essentiality of SEC62/SEC63 |
| AP-MS / BioID | Protein-protein interactions | Interactome of Sec62/Sec63 |
| Cryo-EM | High-resolution structure | Sec61-Sec62-Sec63 complex architecture |
| Molecular dynamics | Conformational changes | Channel gating by Sec62/Sec63 |
| RNA-seq | Transcriptome changes | ER stress response |
| Ribo-seq | Translation efficiency | Posttranslational import substrates |
| Immunofluorescence | Subcellular localization | ER co-localization |
| Western blot | Protein expression | Knockout validation |
CRISPR Knockout and Phenotyping
CRISPR-Cas9 knockout of SEC62, SEC63 or other subunits allows assessment of their essentiality and role in ER protein import. Phenotypic readouts include cell viability, ER stress markers and protein secretion assays.
Proteomics and Interactomics
Affinity purification coupled with mass spectrometry (AP-MS) or proximity labeling (BioID) can identify interacting partners of the Sec62/Sec63 complex. This reveals the broader ER translocation network.
Structural and Computational Modeling
Cryo-EM and molecular dynamics simulations have provided insights into how Sec62 and Sec63 gate the Sec61 channel. These methods are essential for understanding the molecular mechanism.
Transcriptomics and Ribo-seq
RNA-seq and Ribo-seq can measure changes in gene expression and translation efficiency upon Sec62/Sec63 perturbation, revealing downstream effects on the secretory pathway.
How CRISPR Can Be Used to Study GO:0031207 Sec62/Sec63 complex
Knockout
CRISPR knockout of SEC62 or SEC63 in human cell lines can reveal their essentiality. Given the complex's role in ER import, knockouts may be lethal or cause severe growth defects, requiring inducible systems.
Point Mutation
Point mutations identified in ADPLD (e.g., in SEC63) can be introduced via CRISPR base editing or HDR to study their impact on ER protein import and cyst formation.
Knock-in
Tagged knock-in of SEC62 or SEC63 (e.g., with GFP or HA) enables live-cell imaging and proteomic studies without overexpression artifacts.
Overexpression
Overexpression of SEC62 in cancer cell lines can model its oncogenic role and identify downstream signaling pathways.
How EDITGENE Supports Sec62/Sec63 complex Research
Researchers studying Sec62/Sec63 complex-related genes often need to determine whether a candidate gene is causally involved in ER protein import, cancer progression or other diseases. EDITGENE provides a comprehensive suite of CRISPR services to enable such investigations.
Contact EDITGENE today to design your custom CRISPR model for Sec62/Sec63 complex research.
Frequently Asked Questions About Sec62/Sec63 complex
What is the Sec62/Sec63 complex?
The Sec62/Sec63 complex (GO:0031207) is a protein complex involved in the posttranslational targeting of proteins to the endoplasmic reticulum. In yeast, it consists of Sec62p, Sec63p, Sec71p and Sec72p.
What genes are involved in the Sec62/Sec63 complex?
Core genes include SEC62, SEC63, SEC61A1, and in yeast SEC71 and SEC72. Accessory proteins include BiP (HSPA5) and Sec61 subunits.
What is the function of GO:0031207?
GO:0031207 mediates posttranslational ER protein import and regulates the Sec61 channel.
Where is the Sec62/Sec63 complex located?
It is located in the endoplasmic reticulum membrane, associated with the Sec61 translocon.
How does Sec63 function in the complex?
Sec63 contains a J-domain that stimulates the ATPase activity of BiP, driving polypeptide translocation into the ER.
What diseases are associated with Sec62/Sec63 mutations?
Mutations in SEC63 cause autosomal dominant polycystic liver disease. SEC62 and SEC63 are also implicated in cancer.
Is SEC62 essential for cell survival?
Studies in model organisms indicate that Sec62/Sec63 genes are essential for survival, but requirements may vary by cell type.
How can I study the Sec62/Sec63 complex?
CRISPR knockout, point mutation knock-in, overexpression, proteomics and structural biology are common approaches.
What is the difference between Sec62 and Sec63?
Sec62 is involved in signal peptide recognition and channel gating, while Sec63 has a J-domain that activates BiP.
Can I use CRISPR to model Sec62/Sec63-related diseases?
Yes, CRISPR knockout, point mutation and knock-in models are powerful tools for studying these diseases.
Conclusion
The Sec62/Sec63 complex (GO:0031207) is a central component of the ER protein translocation machinery, essential for posttranslational protein import and regulation of the Sec61 channel. Its subunits are implicated in cancer, ADPLD and viral infection, making it a compelling target for basic and translational research. Advances in CRISPR technology and structural biology continue to illuminate its mechanism and disease relevance.
References
- 1. Jung SJ et al.. 2021. Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation.. Int J Mol Sci 22(23) PMID: 34884562
- 2. Linxweiler M et al.. 2017. Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine.. Signal Transduct Target Ther 2:17002 PMID: 29263911
- 3. Itskanov S et al.. 2021. Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62.. Nat Struct Mol Biol 28(2):162-172 PMID: 33398175
- 4. Schorr S et al.. 2020. Identification of signal peptide features for substrate specificity in human Sec62/Sec63-dependent ER protein import.. FEBS J 287(21):4612-4640 PMID: 32133789
- 5. Meyer HA et al.. 2000. Mammalian Sec61 is associated with Sec62 and Sec63.. J Biol Chem 275(19):14550-7 PMID: 10799540
- 6. Bhadra P et al.. 2021. How does Sec63 affect the conformation of Sec61 in yeast?. PLoS Comput Biol 17(3):e1008855 PMID: 33780447
- 7. Liu X et al.. 2025. Sec61s and Sec62/Sec63 Genes Are Essential for Survival by Regulating the Gut and Cuticle Development in Locusta migratoria.. Insects 16(6) PMID: 40558980
- 8. Bhadra P et al.. 2022. Effect of Sec62 on the conformation of the Sec61 channel in yeast.. Biochim Biophys Acta Biomembr 1864(12):184050 PMID: 36116515
