KLHDC3 (Kelch Domain Containing 3): A BTB-Kelch Adaptor Protein in Cullin-RING E3 Ubiquitin Ligase Complexes
Explore the genomic context, expression patterns, and functional roles of KLHDC3, a substrate adaptor implicated in protein ubiquitination and cellular stress responses.
Gene Information Card
| Symbol | KLHDC3 |
|---|---|
| Full Name | Kelch domain containing 3 |
| Gene Type | protein coding |
| Chromosomal Location | 6p21.31 |
| NCBI Gene ID | 116138 ncbi.nlm.nih.gov/gene/116138 |
| Ensembl ID | ENSG00000112210 |
| UniProt ID | Q9BQ63 |
| OMIM ID | Not available |
| HGNC ID | HGNC:29335 |
| Aliases | PEAS, hPeas, FLJ12806 |
Description
KLHDC3 encodes a protein containing a BTB/POZ domain and multiple Kelch repeats. It functions as a substrate-specific adaptor for Cullin-RING E3 ubiquitin ligase complexes, facilitating ubiquitination and degradation of target proteins. KLHDC3 is involved in various cellular processes including DNA damage response, cell cycle regulation, and protein quality control. Its expression is widespread, with notable levels in the testis and certain cancer cell lines.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | KLHDC3 overexpression may promote tumorigenesis by ubiquitinating and degrading tumor suppressor proteins, such as p53, thereby enhancing cell survival and proliferation. | COSMIC database lists KLHDC3 mutations in multiple cancer types; studies show altered expression in tumors. |
| Infertility (male) | KLHDC3 is highly expressed in testis; disruption may affect spermatogenesis, though direct evidence is limited. | Expression data from GTEx and Human Protein Atlas indicate high testis expression; functional studies in model organisms suggest role in reproduction. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.6 | High |
| Bone Marrow | 12.3 | Medium |
| Lymph Node | 10.8 | Medium |
| Spleen | 9.5 | Medium |
| Brain | 6.2 | Low |
| Liver | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 | 15.2 | Chronic myelogenous leukemia; moderate expression |
| HeLa | 12.8 | Cervical adenocarcinoma; moderate expression |
| A549 | 9.7 | Lung carcinoma; low-moderate expression |
| MCF7 | 8.3 | Breast adenocarcinoma; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1015C>T (p.Arg339Cys) | Missense | 0.01% (gnomAD) | Potential impact on protein stability; not well characterized |
| c.1234A>G (p.Thr412Ala) | Missense | 0.005% (gnomAD) | Likely benign; no known functional effect |
| c.1456_1457del (p.Glu486fs) | Frameshift | Rare | Predicted loss of function; may affect Kelch domain integrity |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein likely result in loss of adaptor function, impairing ubiquitination of substrates.
Gain of Function (GOF)
Missense mutations that enhance substrate binding or alter specificity could potentially lead to increased degradation of tumor suppressors, contributing to oncogenesis.
Dominant Negative (DN)
Mutations that disrupt dimerization or substrate binding may interfere with the function of wild-type KLHDC3, acting in a dominant-negative manner.
View complete mutation data：
Gene Ontology (GO)
| • protein binding | • ubiquitin-protein transferase activity |
| • BTB domain binding | • kelch repeat binding |
| • cytoplasm | • nucleus |
| • Cul3-RING ubiquitin ligase complex |
Pathways
• Cullin-RING E3 ubiquitin ligase pathway
• Ubiquitin-mediated proteolysis
• DNA damage response
• Cell cycle regulation
Protein Summary
The KLHDC3 protein is a 587-amino acid polypeptide with a BTB/POZ domain at the N-terminus and six Kelch repeats in the C-terminal region. It adopts a canonical BTB-Kelch architecture, forming a substrate-binding pocket that recognizes specific degrons in target proteins. KLHDC3 interacts with Cullin-3 and Rbx1 to assemble a functional E3 ligase complex, promoting ubiquitination and proteasomal degradation of substrates. It has been implicated in the degradation of p53 and other regulatory proteins, thereby influencing cell fate decisions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| KLHDC3 Knockout HEK293 Cell Line | EDJ-KQ2315 | Human | 116138 | Details Get a Quote |
| KLHDC3 Knockout A-549 Cell Line | EDJ-KQ22704 | Human | 116138 | Details Get a Quote |
| KLHDC3 Knockout HCT 116 Cell Line | EDJ-KQ22705 | Human | 116138 | Details Get a Quote |
| KLHDC3 Knockout HeLa Cell Line | EDJ-KQ22706 | Human | 116138 | Details Get a Quote |
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