EH-domain containing 3 | |
---|---|
Identifiers | |
Symbol | EHD3 |
Alt. symbols | PAST3 |
Alt. names | PAST 3 |
Eps15 homology domain-containing protein 3, abbreviated as EHD3 and also known as PAST3, is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to the EHD protein family, a group of four membrane remodeling proteins related to the Dynamin superfamily of large GTPases. Although the four of them are 70-80% amino acid identical, they all have different locations. [1] Its main function is related to endocytic transport.
Taxonomic identifier | 9606 [NCBI] |
Length (aa) | 535 |
Molecular mass (kDa) | 60.887 |
Molecular weight (g/mol) | 60,887.13 |
Charge | 0.0 |
Isoelectric point | 6.5173 [2] |
Gene type | Protein coding |
Gene location | 2p23.1 |
Exon count | 7 |
Organism | Homo sapiens |
Orthologs | Mice and rats |
The primary structure of a protein is related to which amino acids a protein is made of. EHD3 has 535 amino acids, of which almost three-quarters are common in the four EHD proteins. This protein has a molecular mass of 60887 Daltons.
The secondary structure of the EHD3 protein still remains unknown.
The tertiary structure of a protein involves the domains it is formed of. EHD3 protein is formed of four different domains:
Protein post-translational modifications (PTM) increase the functional diversity of the proteome by the covalent addition of functional groups or proteins, by the hydrolysis of peptide bonds that link amino acids together or by the degradation of different parts of the protein. [6] The EHD3 protein suffers three kinds of amino acid modifications:
The EH domain is a common motif in a family of proteins involved in endocytic trafficking. This family of four paralogs (EHD1-EHD4) has been implicated in receptor intracellular trafficking, particularly in internalization and recycling to the plasma membrane. The list of functions of EHD proteins is just starting to be populated. [8]
EHD3 is a moonlighting protein, which means it can perform different functions depending on the tissue where the protein is located. The main functions are the following:
The gene that encodes the human EHD3 protein is located in chromosome number 2, most specifically in the 23.1 region. On the other hand, the murine EHD3 gene is located in chromosome 17, in the 21st region. The human gene is formed approximately of 35,438 bases. [16]
Both the human and the mouse genes contain a polymorphic (CA) repeat in their 3'UTR. Specifically, human tissue presents two, 4.2- and 3.6-kb, EHD3 RNA species. While the gene is highly expressed in heart and brain, it is moderately expressed in kidney, ovary, liver and placenta.
EHD3 protein has been found in humans and mice. It can be mainly found in human heart and brain, as well as kidney, ovary and liver.
EHD3 (expressed as a green fluorescent fusion protein) was localized in endocytic vesicles, mostly in recycling vesicles, and in membrane tubules, which implicates the N-terminal domain. Therefore, is not rare that this protein regulates the microtubule-dependent movement.
The lack or malfunction of this protein in the human body can cause some diseases such as heart failure [19] or a depressive disorder. Losing EHD3 is also known to be an early step towards glioma formation.
Women are more propense to depressive disorders and anxiety than men, although the reason is still unknown. Still, recent studies have shown the direct relation of some genes and their encoded proteins with the disease, including EHD3. Three SNPs have been found in the gene that are concretely linked to MDD and anxious behaviour exclusively in female patients, which suggest a gender differentiating role in MDD. [20]
Since EHD3 is most abundantly expressed in brain tissues, its role in brain cancer progression has been investigated.
EHD3 gene has got functions as a tumor suppressor gene and the loss of its expression is a very common event in gliomas. The loss of EHD3 transcripts is observed even in the least advanced grades, I and II, suggesting that EHD3 loss is an early event during gliomagenesis. Moreover, EHD3 has growth inhibitory functions and induces a G0/G1 cell cycle arrest and apoptotic death. It is possible that the proapoptotic role of EHD3 involves functions not related to its role in trafficking, but rather to its ATP/GTP-binding ability and possible impact on protein kinase signaling. [21]
The Rab family of proteins is a member of the Ras superfamily of small G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helices. Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.
Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network (TGN) and directly back to the plasma membrane. Mutations in retromer and its associated proteins have been linked to Alzheimer's and Parkinson's diseases.
Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.
Dynamin-1 is a protein that in humans is encoded by the DNM1 gene.
Ras-related protein Rab-8A is a protein that in humans is encoded by the RAB8A gene.
Rab11 family-interacting protein 2 is a protein that in humans is encoded by the RAB11FIP2 gene.
Rab11 family-interacting protein 5 is a protein that in humans is encoded by the RAB11FIP5 gene.
Ras-related protein Rab-11B is a protein that in humans is encoded by the RAB11B gene. Rab11b is reported as most abundantly expressed in brain, heart and testes.
Protein YIF1A is a Yip1 domain family proteins that in humans is encoded by the YIF1A gene.
The EHD protein family is a relatively small group of proteins which have been shown to play a role in several physiological functions, the most notable being the regulation of endocytotic vesicles. This family is recognized by its highly conserved EH domain, a structural motif that has been shown to facilitate specificity and interaction between protein and ligand. The four mammalian EHD proteins that have been classified are: EHD1, EHD2, EHD3, and EHD4.
Transmembrane protein 242 (TMEM242) is a protein that in humans is encoded by the TMEM242 gene. The tmem242 gene is located on chromosome 6, on the long arm, in band 2 section 5.3. This protein is also commonly called C6orf35, BM033, and UPF0463 Transmembrane Protein C6orf35. The tmem242 gene is 35,238 base pairs long, and the protein is 141 amino acids in length. The tmem242 gene contains 4 exons. The function of this protein is not well understood by the scientific community. This protein contains a DUF1358 domain.
RUN and FYVE domain containing 2 (RUFY2) is a protein that in humans is encoded by the RUFY2 gene. The RUFY2 gene is named for two of its domains, the RUN domain and FYVE domains. RUFY2 is a member of the RUFY family of proteins that include RUFY1, RUFY2, RUFY3, and RUFY4. RUFY2 protein has a dynamic role in endosomal membrane trafficking.
Ras and EF-hand domain-containing protein also known as Ras-related protein Rab-45 is a protein that in humans is encoded by the RASEF gene.
EVI5L is a protein that in humans is encoded by the EVI5L gene. EVI5L is a member of the Ras superfamily of monomeric guanine nucleotide-binding (G) proteins, and functions as a GTPase-activating protein (GAP) with a broad specificity. Measurement of in vitro Rab-GAP activity has shown that EVI5L has significant Rab2A- and Rab10-GAP activity.
(HES7) or bHLHb37 is protein coding mammalian gene found on chromosome 17 in humans. HES7 is a member of the Hairy and Enhancer of Split families of Basic helix-loop-helix proteins. The gene product is a transcription factor and is expressed cyclically in the presomitic mesoderm as part of the Notch signalling pathway. HES7 is involved in the segmentation of somites from the presomitic mesoderm in vertebrates. The HES7 gene is self-regulated by a negative feedback loop in which the gene product can bind to its own promoter. This causes the gene to be expressed in an oscillatory manner. The HES7 protein also represses expression of Lunatic Fringe (LFNG) thereby both directly and indirectly regulating the Notch signalling pathway. Mutations in HES7 can result in deformities of the spine, ribs and heart. Spondylocostal dysostosis is a common disease caused by mutations in the HES7 gene. The inheritance pattern of Spondylocostal dysostosis is autosomal recessive.
Uncharacterized protein C12orf60 is a protein that in humans is encoded by the C12orf60 gene. The gene is also known as LOC144608 or MGC47869. The protein lacks transmembrane domains and helices, but it is rich in alpha-helices. It is predicted to localize in the nucleus.
LCHN is a protein that in humans is encoded by the KIAA1147 gene located on chromosome 7. It is likely part of the tripartite DENN domain family of proteins that often function as Rab-GEFs to regulate vesicular trafficking. Both the mRNA and protein have been shown to be upregulated following ischemic stroke, and to be produced at altered levels in patients with FTD-ALS, however the gene's contribution to these states is not well understood.
Single-pass membrane and coiled-coil domain-containing protein 3 is a protein that is encoded in humans by the SMCO3 gene.
Transmembrane protein 155 is a protein that in humans is encoded by the TMEM155 gene. It is located on human chromosome 4, spanning 6,497 bases. It is also referred to as FLJ30834 and LOC132332. This protein is known to be expressed mainly in the brain, placenta, and lymph nodes and is conserved throughout most placental mammals. The function and structure of this protein is still not well understood, but its level of expression has been studied pertaining to various pathologies.
TBC1D30 is a gene in the human genome that encodes the protein of the same name. This protein has two domains, one of which is involved in the processing of the Rab protein. Much of the function of this gene is not yet known, but it is expressed mostly in the brain and adrenal cortex.