WD repeat domain phosphoinositide-interacting protein 4 (WDR45)
The protein contains 360 amino acids for an estimated molecular weight of 39868 Da.
Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:23435086, PubMed:28561066). Activated by the STK11/AMPK signaling pathway upon starvation, WDR45 is involved in autophagosome assembly downstream of WIPI2, regulating the size of forming autophagosomes (PubMed:28561066). Probably recruited to membranes through its PtdIns3P activity (PubMed:28561066). (updated: Dec. 5, 2018)
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.
- 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.
- 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.
(right-click above to access to more options from the contextual menu)
| Variant | Description |
|---|---|
| NBIA5; unknown pathological significance |
Biological Process
Autophagosome assembly
Autophagy
Autophagy of mitochondrion
Autophagy of nucleus
Cellular response to nitrogen starvation
Cellular response to starvation
Protein lipidation
Protein localization to phagophore assembly site
The reference OMIM entry for this protein is 300526
Wd repeat-containing protein 45; wdr45
Wd40 repeat protein interacting with phosphoinositides 4; wipi4
DESCRIPTION
WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI4, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004).CLONING
By searching a genomic database for sequences similar to WIPI1 (609224), followed by RT-PCR of normal testis mRNA, Proikas-Cezanne et al. (2004) cloned WIPI4. The deduced protein contains 7 WD-like repeats. Northern blot analysis detected ubiquitous expression of an approximately 1.8-kb transcript. Highest expression was in heart and skeletal muscle. Proikas-Cezanne et al. (2004) also found that WIPI4 expression was downregulated in a significant portion of renal and pancreatic cancers.MAPPING
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the WIPI4 gene to chromosome Xp11.23. They identified a putative WIPI4 pseudogene at chromosome 4q31.3.GENE FUNCTION
The WDR45 gene has an important role in the autophagy pathway, which is the major intracellular degradation system by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (summary by Saitsu et al., 2013).MOLECULAR GENETICS
In 20 unrelated patients with neurodegeneration with brain iron accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified 19 different de novo heterozygous or hemizygous mutations in the WDR45 gene (see, e.g., 300526.0001-300526.0002). Most of the mutations were truncating, but 2 were missense mutations affecting highly conserved residues. The mutations were located throughout the coding sequence. Initial mutations were identified by exome sequencing and all were confirmed by Sanger sequencing. Seventeen females and 3 males were affected, and the phenotype was similar in all. Since WDR45 is on the X chromosome, Haack et al. (2012) concluded that the males must be somatic mosaic for the mutation, which was demonstrated in 1 affected male. Presumably, males with germline WDR45 mutations are nonviable. Females may either harbor germline or somatic mutations, and several affected females had evidence of skewed X inactivation. These factors may contribute to disease manifestations. Saitsu et al. (2013) identified 5 different de novo heterozygous truncating mutations in the WDR45 gene (see, e.g., 300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial mutations were identified by exome sequencing of 2 patients. Patients had delayed psychomotor development in infancy or early childhood that remained stable until young adulthood when all patients developed further severe motor and cognitive decline, with parkinsonism, dystonia, extrapyramidal signs, and dementia. Most became bedridden with an inability to care for themselves. Brain MRI showed iron accumulation in the globus pallidus and substantia nigra. Lymphoblastoid cells from 4 of the patients showed exclusive expression of the mutant transcript, suggesting X inactivation of the wildtype allele. All patient cells showed decreased levels of the mutant proteins, suggesting protein instability. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, ... More on the omim web site
Dec. 9, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for WDR45
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 300526 was added.