DENN domain-containing protein 1A (DENND1A)
The protein contains 1009 amino acids for an estimated molecular weight of 110577 Da.
Guanine nucleotide exchange factor (GEF) regulating clathrin-mediated endocytosis through RAB35 activation. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form. Regulates clathrin-mediated endocytosis of synaptic vesicles and mediates exit from early endosomes (PubMed:20154091, PubMed:20937701). Binds phosphatidylinositol-phosphates (PtdInsPs), with some preference for PtdIns(3)P (By similarity). (updated: Dec. 20, 2017)
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.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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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Biological Process
Endocytic recycling
Endocytosis
Positive regulation of GTPase activity
Protein transport
Regulation of Rab protein signal transduction
Synaptic vesicle endocytosis
The reference OMIM entry for this protein is 613633
Denn/madd domain-containing protein 1a; dennd1a
Connecdenn
Connecdenn 1
Kiaa1608
DESCRIPTION
Clathrin (see 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010).CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) obtained a partial DENND1A clone, which they designated KIAA1608. RT-PCR ELISA detected ubiquitous DENND1A expression, with highest levels in adult and fetal brain and adult kidney. Within specific adult brain regions, highest expression was detected in hippocampus and thalamus. By database analysis, Allaire et al. (2006) identified mouse Dennd1a, which they called connecdenn. The deduced 1,016-amino acid protein contains an N-terminal DENN domain composed of 3 DENN modules, followed by a PxxP-rich domain. Connecdenn also contains 3 motifs, FSDVF, DPF, and WETFE, for binding to the alpha ear of AP2. Western blot analysis of rat tissues detected connecdenn in brain and testis, but not in several other tissues, including kidney. Immunofluorescence microscopy of cultured rat brain hippocampal neurons showed connecdenn in neuronal cell bodies and along dendrites in a punctate distribution, where it partly colocalized with the presynaptic marker synaptophysin (SYP; 313475). Marat and McPherson (2010) reported that the human connecdenn-1 protein contains 1,009 amino acids. It shares 38% and 32% amino acid identity with human connecdenn-2 (DENND1B; 613292) and -3 (DENND1C; 613634), respectively.GENE FUNCTION
Using coimmunoprecipitation analysis and protein-binding assays, Allaire et al. (2006) found that connecdenn bound rat brain AP2. Mutation analysis revealed that the WETFE motif of connecdenn predominantly mediated binding to the alpha-ear motif of AP2, but that the DPF and FSDVF motifs also contributed. The isolated PxxP domain of connecdenn bound the SH3 domains of endophilin A1 (SH3GL2; 604465) and the endocytic adaptor protein intersectin (ITSN1; 602442), but it did not bind to other SH3 domain-containing proteins. Connecdenn also coimmunoprecipitated with rat brain intersectin and endophilin A1 and was enriched with clathrin-coated vesicles to the same extent as clathrin heavy chain (CLTC; 118955) and AP2. Overexpression and knockdown studies revealed that connecdenn has a role in synaptic vesicle endocytosis. Using a protein pull-down assay with rat brain lysates, Marat and McPherson (2010) showed that connecdenn-1, -2, and -3 bound the terminal domain of clathrin heavy chain. The isolated DENN domains of connecdenn-1 and -2 bound the GDP-bound form of RAB35, and the DENN domains of all 3 connecdenns functioned as GEFs for RAB35. All 3 connecdenns copurified with rat brain clathrin-coated vesicles, although connecdenn-2 and -3 also showed a substantial cytosolic pool. Knockdown of connecdenn-1 or -2 or Rab35 in COS-7 cells resulted in perinuclear clustering and enlargement of early endosomes.MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the DENND1A gene to chromosome 9. Marat and McPherson (2010) stated that the DENND1A gene maps to chromosome 9q33.2. ... More on the omim web site
Feb. 10, 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
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 613633 was added.