EHD3
From Wikipedia, the free encyclopedia
| 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 |
Primary structure
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.
Secondary structure
The secondary structure of the EHD3 protein still remains unknown.
Tertiary structure
The tertiary structure of a protein involves the domains it is formed of. EHD3 protein is formed of four different domains:
- EH domain-containing protein N-terminal, between the 24th and 56th amino acid. This is a short domain that can be found at the beginning of a protein, also known as N-terminus, of many dynamins and EF-hand domain-containing proteins.[3]
- Dynamin-type guanine nucleotide-binding (G) domain, between the 56th and 286th amino acid. It consists of a central eight-stranded beta-sheet surrounded by seven alpha helices and two one-turn helices. It is involved in the binding of magnesium ions (Mg2+) and GTP hydrolysis. GTP is joined to the protein through a nucleotide binding region, located between the 65th and 72nd amino acid.[4]
- EH domain, between the 444th and 532nd amino acid. It is found in all of the EHD proteins. The fold consists of two helix-loop-helix connected by a short antiparallel beta-sheet. The target peptide is bound in a hydrophobic region between two alpha helices. Apart from an EF-hand domain, it can also include tyrosine phosphorylation sites and coiled coils. This domain is often related to the regulation of protein transport, sorting and membrane trafficking.[5]
- EF-hand, between the 476th and 511th amino acid. It forms part of the EH domain. It has a calcium ion (Ca2+) binding, between the 489th and 500th amino acid, which interacts selectively and non-covalently with calcium ions, attaching them to the protein.
Post-translational modifications
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:
- Acetylation. It consists of attaching an acetyl group at the N-terminus.[7] Therefore, the first amino acid is an N-acetylmethionine.
- Cross-link. It involves linking two proteins or two parts of the same protein with covalent bonds. In the case of EHD3, there are two cross-links which are isopeptide bonds between a lysine and a glycine. They are located in the 315th and 511th amino acid.
- Phosphorylation. It consists of the addition of a phosphate group (HPO3). In EHD3, there are two serine phosphorylations; one in the 349th amino acid and other in the 456th.
Functions
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:
- To take part in endocytic transport. The EHD-family proteins have been seen to have a direct relation with endocytic transport in the cell. EHD1 (the closest paralog of EHD3)[9] is in charge of enabling membrane recycling by controlling the way out of internalized molecules from the ERC to the plasma membrane. It has also been found that these EHD proteins bind to the Rab11-effector Rab11-FIP2 via EH-NPF interactions. These associations are affected by their ability to bind nucleotides. The role of EHD1 bonded to the Rab11-effector is clear (stated above), while there has not been found a clear relation between EHD3 and Rab11-FIP2. But when the EHD3 protein underwent a knockdown, the delivery of internalized transferrin and early endosomal proteins to the ERC was prevented, and even the subcellular location of Rab11-FIP2 changed. Therefore, a coordinated role for EHD proteins and Rab11-FIP2 has been found in mediating endocytic recycling and concretely for EHD3, early endosome to ERC transport.[10][11]
- To control the membrane reorganization upon ATP hydrolysis.[12]
- To induce phosphatidic acid membrane tubulation activity.[13]
- To recycle the D1 dopamine receptor.[14]
Gene
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.
