Rho GTPase-activating protein 45 (ARHGAP45)
The protein contains 1136 amino acids for an estimated molecular weight of 124614 Da.
Contains a GTPase activator for the Rho-type GTPases (RhoGAP) domain that would be able to negatively regulate the actin cytoskeleton as well as cell spreading. However, also contains N-terminally a BAR-domin which is able to play an autoinhibitory effect on this RhoGAP activity.', 'Precursor of the histocompatibility antigen HA-1. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. Specifically, mismatching for mHag HA-1 which is recognized as immunodominant, is shown to be associated with the development of severe GVHD after HLA-identical BMT. HA-1 is presented to the cell surface by MHC class I HLA-A*0201, but also by other HLA-A alleles. This complex specifically elicits donor-cytotoxic T-lymphocyte (CTL) reactivity against hematologic malignancies after treatment (updated: Sept. 12, 2018)
Protein identification was indicated in the following studies:
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
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.
This protein is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| allele HA-1H | |
| dbSNP:rs2074442 | |
| dbSNP:rs7251797 | |
| dbSNP:rs36084354 | |
| dbSNP:rs34569196 |
No binding partner found
Biological Process
Activation of GTPase activity
Intracellular signal transduction
Neutrophil degranulation
Regulation of small GTPase mediated signal transduction
Cellular Component
Azurophil granule lumen
Cytosol
Extracellular region
Membrane
Ruffle membrane
Secretory granule lumen
The reference OMIM entry for this protein is 601155
Minor histocompatibility antigen ha-1; hmha1
Histocompatibility (minor) ha-1
Hla-ha1
Kiaa0223
CLONING
Cytotoxic T lymphocytes directed against minor histocompatibility antigens of the host were demonstrated in blood from recipients of bone marrow from donors who were genotypically HLA identical. Clones of such cytotoxic T cells were isolated from lymphocyte populations in the blood of patients with severe graft-versus-host disease (GVHD; see 614395). These clones were used as reagents to identify 5 nonsex-linked minor histocompatibility antigens, designated HA-1, -2 (600642) , -3, -4, and -5 by van Els et al. (1992). Most of the cytotoxic-T-cell clones isolated from various patients reacted against HA-1 (van Els et al., 1992). Goulmy et al. (1996) stated that for immune recognition, the HA-1, -2, -4, and -5 antigens must be presented to cytotoxic T cells by the major histocompatibility antigen HLA-A2. In this way, they behave like antigens recognized in an HLA-restricted fashion. The HA-1 antigen is present in 69% of normal people who express HLA-A2, whereas the frequencies of the 3 others in this set of HLA-A2-restricted minor histocompatibility antigens are either high (95% for HA-2); or low (16% of HA-4 and 7% for HA-5). The HLA-1-restricted minor histocompatibility antigen HA-3 occurs in 88% of persons positive for HLA-A1. HA-1, -2, -4, and -5 are inherited independently of the HLA genes; each of them is encoded by a single gene, and none has a locus within the HLA region (Schreuder et al., 1993).GENE FUNCTION
To investigate whether mismatching of minor histocompatibility antigens contributes to acute GVHD in recipients of genotypically HLA-identical bone marrow, Goulmy et al. (1996) studied 148 bone marrow recipients and their sib donors. Fifty pairs were positive for HLA-A1, 117 were positive for HLA-A2, and 19 were positive for both. The pairs were typed with cytotoxic-T-cell clones specific for HA-1, -2, -3, -4, and -5. A mismatch of only HA-1 was significantly correlated with GVHD of grade II or higher in adults. Den Haan et al. (1998) identified HA-1 as a nonapeptide derived from a partial cDNA sequence, designated KIAA0223, derived from the acute myelogenous leukemia KG-1. HA-1 has the amino acid sequence VLHDDLLEA, termed HA-1(H). A single amino acid substitution of arginine for histidine leads to HA-1-negative status, termed HA-1(R). Den Haan et al. (1998) found that HA-1(H) is presented by its recognizing antigen, HLA-A*0201, while HA-1(R) is not. The binding affinity of the HA-1(R) peptide for HLA-A*0201 is 1/12 that of HA-1(H). The authors concluded that HA-1(R) is a null allele and that only bone marrow transplantation from an HA-1(R/R) donor to an HA-1(H/H) or HA-1(H/R) recipient, and not the reverse, would be significantly associated with GVHD. Den Haan et al. (1998) suggested that HA-1 typing before bone marrow transplantation of HLA-matched donor-recipient combinations would improve bone marrow donor selection and prediction of HA-1-induced GVHD.GENE STRUCTURE
Kaminski et al. (2000) determined that the HA-1 gene contains 23 exons and spans 16 kb.MAPPING
By radiation hybrid analysis, Nagase et al. (1996) mapped the KIAA0223 gene to chromosome 19. Kaminski et al. (2000) mapped the HA-1 gene to chromosome 19p13.3 based on sequence identity shared with a BAC clone mapped to 19p13.3. ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 601155 was added.
Feb. 23, 2019: Protein entry updated
Automatic update: model status changed
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).