COL4A3BP Human
Description
Introduction
COL4A3BP (collagen type IV alpha-3-binding protein), also known as ceramide transfer protein (CERT) or STARD11, is a multifunctional protein encoded by the COL4A3BP gene. It plays dual roles in autoimmunity and lipid metabolism, serving as both a kinase targeting the Goodpasture antigen and a ceramide transfer protein critical for sphingolipid biosynthesis. This article integrates structural, functional, and clinical insights into COL4A3BP, supported by experimental data and recent research findings.
2.1. Protein Domains and Motifs
COL4A3BP contains three key structural domains essential for its functions:
The full-length protein is ~68 kDa, though recombinant variants (e.g., 290 amino acids) are truncated for experimental use .
2.2. Gene Structure
The COL4A3BP gene is located on chromosome 5q13.3 and produces three transcript variants through alternative splicing . Two major isoforms include:
| Isoform | Description | Function | References |
|---|---|---|---|
| GPBP | Full-length protein | Phosphorylates collagen IV; anti-apoptotic roles | |
| GPBPΔ26 | Lacks 26-amino acid serine-rich domain | Ceramide transfer (CERT activity) |
3.1. Ceramide Transport
COL4A3BP facilitates non-vesicular ceramide transfer from the ER to the Golgi via a three-step mechanism:
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START Domain: Extracts ceramide from ER membranes.
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PH Domain: Binds PI4P on Golgi membranes for targeting.
This process is ATP-dependent and regulated by phosphorylation. Overexpression of OSBP competes for PI4P binding, inhibiting ceramide transport .
3.2. Autoimmune Regulation
As a kinase, COL4A3BP phosphorylates the N-terminal region of the alpha-3 chain of collagen IV (Goodpasture antigen). This activity is central to:
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Goodpasture’s Disease: Autoantibodies targeting the phosphorylated antigen cause renal/lung damage .
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TNF-α Signaling: TNF-α upregulates COL4A3BP via NF-κB, linking inflammation to autoimmunity .
3.3. Developmental and Cellular Roles
4.1. Phosphorylation
COL4A3BP’s activity is controlled by phosphorylation at the serine-rich (SR) motif:
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Activation: Dephosphorylated by PP2Cε (ER-localized phosphatase).
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Inhibition: Phosphorylated by PKD and casein kinases, inducing autoinhibition via PH-START domain interaction .
4.2. Inhibitors
| Inhibitor | Mechanism | Impact | References |
|---|---|---|---|
| HPA-12 | Blocks ATP-dependent ceramide transfer | Reduces sphingomyelin synthesis |
5.1. Autoimmune Diseases
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Goodpasture’s Syndrome: Autoantibodies target the phosphorylated collagen IV NC1 domain .
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GBM Collagen IV Organization: NZW mice develop IgA deposits and collagen IV disorganization with elevated GPBP .
5.2. Cancer and Neurodegeneration
While direct evidence is limited, COL4A3BP’s role in ceramide metabolism and apoptosis suggests potential links to:
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Cancer Progression: Altered sphingolipid profiles in tumors.
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Neurodegeneration: Ceramide imbalance in brain pathologies .
6.1. Recombinant Protein Applications
The recombinant COL4A3BP (290 a.a., 33.1 kDa) is used in studies of ceramide transfer and kinase activity .
| Property | Value | Conditions | References |
|---|---|---|---|
| Purity | >95% (SDS-PAGE) | Proprietary chromatography | |
| Stability | 4°C (2–4 weeks); −20°C (long-term) | 20 mM Tris-HCl, 0.1 M NaCl, 10% glycerol |
6.2. Gene Interactions
The COL4A3BP gene is head-to-head with POLK (kappa DNA polymerase), sharing a TNF-α-responsive promoter. This genetic arrangement may link DNA repair and autoimmune pathways .
Product Specs
Product Science Overview
Collagen Type IV Alpha 3 Binding Protein, also known as COL4A3BP or Goodpasture antigen-binding protein, is a significant protein in the human body. It plays a crucial role in the structural integrity of basement membranes, particularly in the glomerular basement membrane (GBM) of the kidneys. This article delves into the background, structure, function, and clinical significance of this protein.
Collagen Type IV is a major structural component of basement membranes, forming a network-like structure. It is composed of three alpha subunits, encoded by six different genes (alpha 1 through alpha 6). The alpha 3 subunit, encoded by the COL4A3 gene, is a critical component of this structure . The recombinant form of this protein is produced in insect cells and is available in a highly purified form, suitable for various research applications .
The primary function of Collagen Type IV Alpha 3 is to provide structural support to basement membranes. It forms a ‘chicken-wire’ meshwork along with other proteins such as laminins, proteoglycans, and entactin/nidogen . This meshwork is essential for the filtration function of the glomerular basement membrane in the kidneys.
Collagen Type IV Alpha 3 is associated with several clinical conditions. In Goodpasture syndrome, autoantibodies target the collagen molecules in the basement membranes of alveoli and glomeruli, leading to kidney and lung damage . The epitopes that elicit these autoantibodies are primarily located in the non-collagenous C-terminal domain of the protein . Additionally, mutations in the COL4A3 gene are linked to an autosomal recessive form of Alport syndrome, a genetic disorder affecting the kidneys, eyes, and ears .
The recombinant form of Collagen Type IV Alpha 3 is produced using Sf9 insect cells and is available in a sterile filtered clear solution . It is used in various diagnostic assays, including ELISA, to detect autoantibodies in patients with Goodpasture syndrome . The recombinant protein is also suitable for biotinylation and iodination, making it a versatile tool for research and diagnostic purposes .
