Path: /proteins/hnrnp-a2b1-protein
Title: HNRNP-A2B1 Protein
Tags: section:proteins, kind:protein
| HNRNP-A2B1 Protein |
|---|
| Gene | [HNRNPA2B1](/genes/hnrnpa2b1) |
| UniProt ID | [P22626](https://www.uniprot.org/uniprot/P22626) |
| PDB Structures | 1L5K, 2A38 |
| Molecular Weight | ~37 kDa (A2), ~43 kDa (A2B1) |
| Subcellular Localization | Nucleus, cytoplasm, stress granules |
| Protein Family | HnRNP A/B family, RNA-binding proteins |
| Length | 353 amino acids (A2), 390 amino acids (A2B1) |
| Associated Diseases | ALS, FTD, MSD, RA |
HNRNP-A2B1 (Heterogeneous Nuclear Ribonucleoprotein A2/B1) is an RNA-binding protein that plays essential roles in RNA splicing, transport, and translation. Dominant missense mutations cause multisystemic proteinopathy (MSP), a rare disorder with features of inclusion body myopathy, Paget disease of bone, and frontotemporal dementia, as well as familial ALS.
HNRNP-A2B1 is a 353-390 amino acid protein (depending on isoform) with key structural features:
- RRM1 (RNA recognition motif 1): N-terminal RNA-binding domain (amino acids 103-179)
- RRM2 (RNA recognition motif 2): C-terminal RNA-binding domain (amino acids 192-259)
- Glycine-rich domain: Low-complexity region prone to aggregation (amino acids 269-341)
- Prion-like domain: Facilitates phase separation into stress granules
- Nuclear localization signal: Basic region for nuclear import
HNRNP-A2B1 performs critical functions in RNA biology:
- Alternative splicing: Major regulator of alternative splicing, particularly for neuronal transcripts
- RNA transport: Facilitates cytoplasmic transport of mRNAs
- RNA stability: Regulates mRNA half-life and translation
- Telomere function: Component of telomerase RNP complex
- Stress response: Rapidly localizes to stress granules under cellular stress
- Immune regulation: Regulates innate immune responses and cytokine production
HNRNP-A2B1 mutations cause MSP, characterized by:
- Inclusion body myopathy: Progressive muscle weakness starting in adulthood
- Paget disease of bone: Increased bone turnover and deformities
- Frontotemporal dementia: Cognitive and behavioral changes
- Motor neuron disease: Some patients develop ALS features
HNRNP-A2B1 mutations cause familial ALS:
- Cytoplasmic inclusions: Mutant protein forms aggregates in motor neurons
- RNA processing defects: Aberrant splicing of essential neuronal genes
- Stress granule pathology: Dysregulated stress granule dynamics
- TDP-43 pathology: Often co-localizes with TDP-43 inclusions
- RNA splicing disruption: Aberrant processing of transcripts essential for neuronal survival
- Stress granule dysfunction: Persistent granules become pathogenic aggregates
- Loss of nuclear function: Sequestration in cytoplasm reduces nuclear RNA processing
- Protein aggregation: Formation of insoluble cytoplasmic inclusions
- Cellular transport defects: Impaired RNA and ribonucleoprotein trafficking
Current therapeutic approaches include:
- Antisense oligonucleotides: Targeting mutant HNRNPA2B1 expression
- RNA splicing modulators: Correct aberrant splicing patterns
- Stress granule inhibitors: Modulate stress granule dynamics
- Protein aggregation blockers: Prevent formation of toxic aggregates
- Gene therapy: AAV-delivered therapeutic approaches