Rho GDP-dissociation inhibitor 1 (ARHGDIA)
The protein contains 204 amino acids for an estimated molecular weight of 23207 Da.
Controls Rho proteins homeostasis. Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an inactive cytosolic pool, regulating their stability and protecting them from degradation. Actively involved in the recycling and distribution of activated Rho GTPases in the cell, mediates extraction from membranes of both inactive and activated molecules due its exceptionally high affinity for prenylated forms. Through the modulation of Rho proteins, may play a role in cell motility regulation. In glioma cells, inhibits cell migration and invasion by mediating the signals of SEMA5A and PLXNB3 that lead to inactivation of RAC1. (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Movement of cell or subcellular component
Negative regulation of apoptotic process
Negative regulation of axonogenesis
Negative regulation of cell adhesion
Negative regulation of cell migration
Neurotrophin TRK receptor signaling pathway
Positive regulation of axonogenesis
Positive regulation of GTPase activity
Regulation of actin cytoskeleton reorganization
Regulation of axonogenesis
Regulation of protein localization
Regulation of Rho protein signal transduction
Regulation of small GTPase mediated signal transduction
Rho protein signal transduction
Semaphorin-plexin signaling pathway
Small GTPase mediated signal transduction
Molecular Function
GTPase activator activity
Rac GTPase binding
Rho GDP-dissociation inhibitor activity
The reference OMIM entry for this protein is 601925
Rho gdp-dissociation inhibitor alpha; arhgdia
Rhogdi
Gdp-dissociation inhibitor, aplysia ras-related 1; gdia1
DESCRIPTION
The ARHGDIA gene encodes the Rho-GDP dissociation inhibitor-alpha, which sequesters Rho-GTPases in an inactive state in the cytosol (summary by Gupta et al., 2013). Aplysia Ras-related homologs (ARHs), also called Rho genes, belong to the RAS gene superfamily encoding small guanine nucleotide exchange (GTP/GDP) factors. The ARH proteins may be kept in the inactive, GDP-bound state by interaction with GDP dissociation inhibitors, such as ARHGDIA (Leffers et al., 1993).CLONING
By screening a transformed amnion cell library with an ARHGDIB (602843) cDNA, Leffers et al. (1993) isolated cDNAs encoding ARHGDIA. They found that ARHGDIA corresponded to a protein in the keratinocyte 2-dimensional-gel protein database known as IEF (isoelectric focusing) 8118. By 2-dimensional gel electrophoresis, the predicted 204-amino acid protein had a pI of 4.74 and migrated at 29 kD. The amino acid sequences of human and bovine ARHGDIA are 97% identical. Northern blot analysis revealed that ARHGDIA was expressed in all cell lines and tissues tested.GENE STRUCTURE
Leffers et al. (1993) found that the ARHGDIA gene contains 6 exons.MAPPING
Wagner et al. (1997) demonstrated by fluorescence in situ hybridization that the ARHGDIA gene maps to chromosome 17q25.3. The assignment was confirmed by the use of a new somatic cell hybrid panel for chromosome 17q.GENE FUNCTION
Leffers et al. (1993) found that overexpression of ARHGDIB in mammalian cells caused them to 'round up' and disrupted the actin cytoskeleton, mimicking the phenotypic changes associated with inactivation of Rho proteins. Using immunohistochemistry, Gupta et al. (2013) found that the Arhgdia protein was highly expressed in the glomerulus of the adult mouse kidney, where it localized to podocytes. The protein was also detected in mesangial cells. Mouse podocytes with knockdown of the Arhgdia gene using shRNA showed higher levels of activated RhoA (165390), Rac1 (602048), and Cdc42 (116952) compared to control cells. These findings demonstrated that those Rho-GTPases were no longer maintained in their inactive state in the absence of functional Arhgdia. Further studies showed that these cells had impaired cell motility, as demonstrated by impaired wound healing, likely due to altered actin dynamics.MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital nephrotic syndrome (NPHS8; 615244), Gupta et al. (2013) identified a homozygous 3-bp in-frame deletion in the ARHGDIA gene (601925.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional studies and studies of patient fibroblasts showed that the mutation resulted in the hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and impaired cell motility. Both girls presented in the first weeks of life with severe nephrotic syndrome, resulting in death in one. Renal biopsy of 1 patient showed diffuse mesangial sclerosis. The findings suggested that the mutation caused an imbalance in the active and inactive forms of Rho-GTPases, leading to derangements in the actin cytoskeleton within podocytes and subsequent nephrotic syndrome. Gupta et al. (2013) noted that Arhgdia-null mice also develop proteinuria and progressive renal failure. By homozygosity mapping and exome sequencing in 2 sibs of Ashkenazi Jewish descent with early-onset steroid-resistant nephrotic syndrome with diffus ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601925 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed