D-domain (Dimerization domain) is found in the upstream of the

F-box domain F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome. Core ...

, which is a conserved

dimerization A dimer () ('' di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular. Dimers also have significant implications in polymer chemistry, inorganic ch ...

motif located in

WD40 WD-40 is an American brand and the trademark of a penetrating oil manufactured by the WD-40 Company based in San Diego, California. The formula for WD-40 was invented for the Rocket Chemical Company as early as 1953 before it evolved into the ...

repeat F box proteins, such as Cdc4, Met30, β-TrCP and Pop1/2. But Vts1, a RNA binding protein at the

SAM domain In molecular biology, the protein domain Sterile alpha motif (or SAM) is a putative protein interaction module present in a wide variety of proteins involved in many biological processes. The SAM domain that spreads over around 70 residues is fo ...

found in yeast contain D-domain though it does not have any F-box domain. As targeting domain or docking site, D-domain is found in the ETS-domain transcription factor Elk-1. It is distinct from the phospho-acceptor motifs and plays a crucial function in the efficient phosphorylation and activation of Elk-1 by

MAP kinases A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

(MAPKs) such as extracellular signal-regulated protein kinase (ERK),

JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are re ...

, mitogen and stress-activated protein kinase-1, and

ribosomal S6 kinase In molecular biology, ribosomal s6 kinase (rsk) is a family of protein kinases involved in signal transduction. There are two subfamilies of rsk, p90rsk, also known as MAPK-activated protein kinase-1 (MAPKAP-K1), and p70rsk, also known as S6-H1 K ...

. Additionally this domain can be incorporated into

chimeric antigen receptor In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specifi ...

(CAR) designs for T cell therapies that allows for the specific recognition and binding of target antigens, such as

CD123 The interleukin-3 receptor ( CD123) is a molecule found on cells which helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system. The gene coding for the receptor is located in the pseudoautosomal region of th ...

, which is a potential therapeutic target for hematologic malignancies like

acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include ...

(AML).

Core components

D-domain is formed up of three

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earli ...

which generate a parallel dimer by self-associating in a right-handed super-helical way. There are two possible configurations for this domain's N terminus; those are an unstructured loop and an amphipathic alpha-helix (H0). Interactions with the adjacent

thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also hav ...

ligand-binding domain In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

's (TR-LBD), AF-2 coactivator-binding groove are necessary for the creation of the H0 structure of D-domain. While additional

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

residues are crucial only for

JNKs c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylation, phosphorylate c-Jun on serine, Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein k ...

, residues in the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

end of the D-domain are significant for not only JNK MAPKs but also ERK. The unique topology of D-domain enables it to target epitopes that may not be accessible to

scFv A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten t ...

CDR loops, offering the potential for improved

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

recognition.

Function

D-domain can interconnect with another D-domain which belongs to indistinguishable protein. This type of interactions is called homotypic interactions. For instance, this kind of domain is important for the interaction of a subclass of F-box proteins which is named after WD40. This arranges in the π-system configuration that is known as suprafacial configuration which is observed between E2-site of every SCF protomer and the substrate-binding site. D-domain is also involved in the self-efficient binding of Fbw7 and stable dimerization of

cyclin E Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase, G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphoryla ...

T380 phospho-degron to Fbw7. Dimerization of β-TrCP1 and β-TrCP2 also found in NH₂-terminal of D-domain. This domain in the thyroid hormone receptor (TR) connects the

DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...

(DBD) with the ligand-binding domain (LBD). It can form functionally useful extensions of the DBD and LBD. It also can unfold for the purpose of allowing TRs to adjust to various DNA response components and have the ability to substantially control rotational flexibility and TR DNA binding activity. This domain also serves as a JNK-binding motif, with variations in the respective kinase binding capacity observed between the c-Jun D-domain and the Elk-1 D-domain. The cytoplasmic region of the receptor for modern glycation end-products (

RAGE Rage may refer to: * Rage (emotion), an intense form of anger Games * Rage (collectible card game), a collectible card game * Rage (trick-taking card game), a commercial variant of the card game Oh Hell * ''Rage'' (video game), a 2011 first-per ...

) contains a sequence similar to the D-domain, which is important for the direct interaction between ERK and RAGE. This interaction is independent of the phosphorylation status of ERK and is conserved across species. Targeting via this increases the specificity and efficiency of the MAP kinase signal transduction pathway. D-domain

CARs A car or automobile is a motor vehicle with wheels. Most definitions of ''cars'' say that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people instead of goods. The year 1886 is regarded as t ...

have demonstrated potent

antitumor Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g. ...

activity in

xenograft Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograf ...

models, leading to complete durable remission in AML models. It can also be used to generate functional, bi-specific CARs by combining them with other specific targeting domains, such as a

CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...

-specific scFv.

Regulation

Mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

in the D-domain can selectively inhibit TR interactions with specific DNA response elements and affect TR activity. In addition, it can be engineered to be less immunogenic by removing putative T cell epitopes, potentially reducing the risk of antigen-independent exhaustion. On the other hand, trivial effect on phosphorylation is observed due to mutation at the D-domain of p38MAPKs, which signifies the inertness of this domain to the interaction of Elk-1 to p38 MAPKs. Also, dimerization of the

SCF complex Skp, Cullin, F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has impo ...

facilitated by the D-domain shows insignificant overtly impact on catalytic competence or substrate affinity but enhances lysine acceptor site utilization.

References

{{reflist Protein domains