# D domain

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{{Short description|Protein domain}}

'''D-domain''' (Dimerization domain)  is found in the upstream of the [F-box domain](/source/F-box_protein), which is a conserved [dimerization](/source/protein_dimer) motif located in [WD40](/source/WD40_repeat) repeat F box proteins, such as [Cdc4](/source/Cell_division_control_protein_4), Met30, [β-TrCP](/source/%CE%B2-TrCP) and [Pop1/2](/source/POP1_(gene)).<ref name=":0">{{Cite journal |last1=Tang |first1=Xiaojing |last2=Orlicky |first2=Stephen |last3=Lin |first3=Zhenyuan |last4=Willems |first4=Andrew |last5=Neculai |first5=Dante |last6=Ceccarelli |first6=Derek |last7=Mercurio |first7=Frank |last8=Shilton |first8=Brian H. |last9=Sicheri |first9=Frank |last10=Tyers |first10=Mike |date=June 2007 |title=Suprafacial Orientation of the SCFCdc4 Dimer Accommodates Multiple Geometries for Substrate Ubiquitination |journal=Cell |volume=129 |issue=6 |pages=1165–1176 |doi=10.1016/j.cell.2007.04.042 |issn=0092-8674|doi-access=free |pmid=17574027 }}</ref><ref name=":4">{{Cite journal |last1=Suzuki |first1=Hiroshi |last2=Chiba |first2=Tomoki |last3=Suzuki |first3=Toshiaki |last4=Fujita |first4=Takashi |last5=Ikenoue |first5=Tsuneo |last6=Omata |first6=Masao |last7=Furuichi |first7=Kiyoshi |last8=Shikama |first8=Hisataka |last9=Tanaka |first9=Keiji |date=January 2000 |title=Homodimer of Two F-box Proteins βTrCP1 or βTrCP2 Binds to IκBα for Signal-dependent Ubiquitination |journal=Journal of Biological Chemistry |volume=275 |issue=4 |pages=2877–2884 |doi=10.1074/jbc.275.4.2877 |issn=0021-9258 |doi-access=free |pmid=10644755 }}</ref> But [Vts1](/source/Vts1), a RNA binding protein at the [SAM domain](/source/SAM_domain) found in yeast contain D-domain though it does not have any F-box domain.<ref>{{Cite journal |last1=Aviv |first1=Tzvi |last2=Lin |first2=Zhen |last3=Lau |first3=Stefanie |last4=Rendl |first4=Laura M. |last5=Sicheri |first5=Frank |last6=Smibert |first6=Craig A. |date=August 2003 |title=The RNA-binding SAM domain of Smaug defines a new family of post-transcriptional regulators |url=https://www.nature.com/articles/nsb956 |journal=Nature Structural & Molecular Biology |language=en |volume=10 |issue=8 |pages=614–621 |doi=10.1038/nsb956 |issn=1545-9985|url-access=subscription }}</ref>

As targeting domain or docking site, D-domain is found in the [ETS-domain](/source/ETS_transcription_factor_family) transcription factor [Elk-1](/source/ELK1). 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](/source/MAP_kinases) (MAPKs) such as [extracellular signal-regulated protein kinase (ERK)](/source/Extracellular_signal-regulated_kinases), [JNK](/source/C-Jun_N-terminal_kinases),<ref name=":1">{{Cite journal |last=Yang |first=S.-H. |date=1998-03-16 |title=Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1 |url=http://emboj.embopress.org/cgi/doi/10.1093/emboj/17.6.1740 |journal=The EMBO Journal |volume=17 |issue=6 |pages=1740–1749 |doi=10.1093/emboj/17.6.1740 |pmc=1170521 |pmid=9501095}}</ref> mitogen and stress-activated protein kinase-1, and [ribosomal S6 kinase](/source/Ribosomal_s6_kinase).<ref name=":2">{{Cite journal |last1=Ishihara |first1=Katsuya |last2=Tsutsumi |first2=Kae |last3=Kawane |first3=Shiho |last4=Nakajima |first4=Motowo |last5=Kasaoka |first5=Tatsuhiko |date=2003-08-28 |title=The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site |url=https://febs.onlinelibrary.wiley.com/doi/10.1016/S0014-5793%2803%2900846-9 |journal=FEBS Letters |language=en |volume=550 |issue=1–3 |pages=107–113 |doi=10.1016/S0014-5793(03)00846-9 |pmid=12935895 |issn=0014-5793|url-access=subscription }}</ref>

Additionally this domain can be incorporated into [chimeric antigen receptor](/source/chimeric_antigen_receptor) (CAR) designs for T cell therapies that allows for the specific recognition and binding of target antigens, such as [CD123](/source/Interleukin-3_receptor), which is a potential therapeutic target for hematologic malignancies like [acute myelogenous leukemia](/source/Acute_myeloid_leukemia) (AML).<ref name=":3">{{Cite journal |last1=Qin |first1=Haiying |last2=Edwards |first2=Justin P. |last3=Zaritskaya |first3=Liubov |last4=Gupta |first4=Ankit |last5=Mu |first5=C. Jenny |last6=Fry |first6=Terry J. |last7=Hilbert |first7=David M. |last8=LaFleur |first8=David W. |date=July 2019 |title=Chimeric Antigen Receptors Incorporating D Domains Targeting CD123 Direct Potent Mono- and Bi-specific Antitumor Activity of T Cells |url=https://doi.org/10.1016/j.ymthe.2019.04.010 |journal=Molecular Therapy |volume=27 |issue=7 |pages=1262–1274 |doi=10.1016/j.ymthe.2019.04.010 |issn=1525-0016 |pmc=6612629 |pmid=31043341}}</ref>

== Core components ==
D-domain is formed up of three [alpha helices](/source/Alpha_helix) which generate a parallel dimer by self-associating in a right-handed super-helical way.<ref name=":0" /> 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](/source/thyroid_hormone_receptor) [ligand-binding domain](/source/ligand-binding_domain)'s (TR-LBD), [AF-2 coactivator](/source/Ligand_binding_domain)-binding groove are necessary for the creation of the H0 structure of D-domain.<ref name=":5">{{Cite journal |last1=Nascimento |first1=Alessandro S. |last2=Dias |first2=Sandra Martha Gomes |last3=Nunes |first3=Fábio M. |last4=Aparício |first4=Ricardo |last5=Ambrosio |first5=Andre L. B. |last6=Bleicher |first6=Lucas |last7=Figueira |first7=Ana Carolina M. |last8=Santos |first8=Maria Auxiliadora M. |last9=Neto |first9=Mário de Oliveira |last10=Fischer |first10=Hannes |last11=Togashi |first11=Marie |last12=Craievich |first12=Aldo F. |last13=Garratt |first13=Richard C. |last14=Baxter |first14=John D. |last15=Webb |first15=Paul |date=2006-07-14 |title=Structural Rearrangements in the Thyroid Hormone Receptor Hinge Domain and Their Putative Role in the Receptor Function |url=https://www.sciencedirect.com/science/article/pii/S0022283606005742 |journal=Journal of Molecular Biology |volume=360 |issue=3 |pages=586–598 |doi=10.1016/j.jmb.2006.05.008 |pmid=16781732 |issn=0022-2836|url-access=subscription }}</ref> While additional [C-terminal](/source/C-terminus) residues are crucial only for [JNKs](/source/C-Jun_N-terminal_kinases), residues in the [N-terminal](/source/N-terminus) end of the D-domain are significant for not only JNK MAPKs but also ERK.<ref name=":1" /><ref name=":2" />

The unique topology of D-domain enables it to target [epitopes](/source/Epitope_spreading) that may not be accessible to [scFv](/source/Single-chain_variable_fragment) [CDR](/source/CRD-BP) loops, offering the potential for improved [antigen](/source/antigen) recognition.<ref name=":3" />

== 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](/source/E_site) of every [SCF](/source/SCF_complex) protomer and the substrate-binding site.<ref name=":0" /> D-domain is also involved in the self-efficient binding of [Fbw7](/source/FBXW7) and stable dimerization of [cyclin E](/source/cyclin_E) T380 phospho-degron to Fbw7.<ref>{{Cite journal |last1=Welcker |first1=Markus |last2=Clurman |first2=Bruce E. |date=2007-02-13 |title=Fbw7/hCDC4 dimerization regulates its substrate interactions |journal=Cell Division |volume=2 |issue=1 |pages=7 |doi=10.1186/1747-1028-2-7 |issn=1747-1028 |pmc=1802738 |pmid=17298674 |doi-access=free }}</ref> Dimerization of β-TrCP1 and β-TrCP2 also found in NH<sub>2</sub>-terminal of D-domain.<ref name=":4" /> This domain in the thyroid hormone receptor (TR) connects the [DNA-binding domain](/source/DNA-binding_domain) (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.<ref name=":5" /> 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.<ref name=":1" /> The cytoplasmic region of the receptor for modern glycation end-products ([RAGE](/source/RAGE_(receptor))) 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.<ref name=":2" /> Targeting via this increases the specificity and efficiency of the MAP kinase signal transduction pathway.<ref>{{Cite journal |last1=Yang |first1=Shen-Hsi |last2=Yates |first2=Paula R. |last3=Whitmarsh |first3=Alan J. |last4=Davis |first4=Roger J. |last5=Sharrocks |first5=Andrew D. |date=1998-02-01 |title=The Elk-1 ETS-Domain Transcription Factor Contains a Mitogen-Activated Protein Kinase Targeting Motif |journal=Molecular and Cellular Biology |language=en |volume=18 |issue=2 |pages=710–720 |doi=10.1128/MCB.18.2.710 |issn=1098-5549 |pmc=108782 |pmid=9447967}}</ref>

D-domain [CARs](/source/CAR_T_cell) have demonstrated potent [antitumor](/source/antitumor) activity in [xenograft](/source/Xenotransplantation) 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](/source/CD19)-specific scFv.<ref name=":3" />

== Regulation ==
[Mutations](/source/Mutation) in the D-domain can selectively inhibit TR interactions with specific DNA response elements and affect TR activity.<ref name=":5" /> In addition, it can be engineered to be less immunogenic by removing putative T cell epitopes, potentially reducing the risk of antigen-independent exhaustion.<ref name=":3" /> On the other hand, trivial effect on phosphorylation is observed due to mutation at the D-domain of [p38MAPKs](/source/P38_mitogen-activated_protein_kinases), which signifies the inertness of this domain to the interaction of Elk-1 to p38 MAPKs.<ref name=":1" /> Also, dimerization of the [SCF complex](/source/SCF_complex) facilitated by the D-domain shows insignificant overtly impact on catalytic competence or substrate affinity but enhances lysine acceptor site utilization.<ref name=":0" />

== References ==

{{reflist}}

Category:Protein domains

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Adapted from the Wikipedia article [D domain](https://en.wikipedia.org/wiki/D_domain) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/D_domain?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.