Sandbox Reserved 1726

From Proteopedia

(Difference between revisions)

Revision as of 01:54, 19 April 2022

This Sandbox is Reserved from February 28 through September 1, 2022 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1700 through Sandbox Reserved 1729.

To get started:

Click the edit this page tab at the top. Save the page after each step, then edit it again.
show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

Anaplastic Lymphoma Kinase Extracellular Region

1 Background
2 Structure
3 Function
4 Disease and Medical Relevance
- 4.1 Cancer
  - 4.1.1 Pediatric Neuroblastoma

Background

Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor and a member of the family of Receptor Tyrosine Kinases (RTKs). RTKs are a family of biomolecules that are primarily responsible for biosignaling pathways such as the insulin signaling pathway. ALK was identified as a novel tyrosine phosphoprotein in 1994 in an analysis of Anaplastic Large-Cell Lymphoma, the protein's namesake. A full analysis and characterization of ALK was completed in 1997, properly identifying it as a RTK, and linking it closely to Leukocyte Tyrosine Kinase (LTK).

Structure

ALK is a close homolog of LTK, and together these two homologues constitute a subgroup within the superfamily of insulin receptors (IR). ALK is composed of three primary regions: the extracellular region, the transmembrane region, and the intracellular region.

Figure 1. Overview of Anaplastic Lymphoma Kinase Structure with domains where known structure are color coordinated and other domains are grayed out.

The extracellular region of ALK contains 8 total domains within 2 fragments. A Three Helix Bundle-like domain (THB-like), a Poly-Glycine domain (GlyR), a Tumor Necrosis Factor-like domain (TNF-like), and an Epidermal Growth Factor-like domain (EGF-like) make up the ligand binding fragment while a N-terminal domain, two meprin–A-5 protein–receptor protein tyrosine phosphatase μ (MAM) domains and a low-density lipoprotein receptor class A (LDL) domain sandwiched between the two MAM domains make up the second fragment. All four domains of the ligand binding fragment of the extracellular region contribute to ligand-binding ^[1]. The presence of an LDL domain sandwiched by two MAM domains is a unique feature that ALK does not share with other RTKs. The purpose behind this unique difference is still unclear. The transmembrane helical region (TMH) bridges the gap between the intracellular and extracellular regions. The intracellular tyrosine kinase domain features the Kinase domain and the C-terminal end (Figure 1).

Domains

Three Helix Bundle-like Domain

The mainly has a structural function as it interacts with the TNF-like domain upon ligand binding. The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain. This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding. The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. ^[2]

Poly-Glycine Domain

Figure 2. Rare Glycine helices on Anaplastic Lymphoma Kinase

Located between the THB-like domain and the TNF-like domain, the has an important structural role. The GlyR domain also has a rare and unique structure of left-handed glycine helices with hexagonal hydrogen bonding shown in Figure 2. These 14 glycine helices are unique to ALK's function among other tyrosine kinases, as these types of structures on the binding domain are not present. These helices are rigid structures, providing a strong anchor for the ligand binding site while the other domains undergo drastic conformational rearrangements.^[2]

Tumor-Necrosis Factor-like Domain

The interacts with the THB-like domain to begin the conformational changes associated with ligand binding. It is located in approximately the midregion of the extracellular region, bridging the gap between the GlyR domain and the EGF-like domain. This domain also assists in mediating ligand binding with the EGF-like domain. In ligand-binding, as previously stated, this domain interacts heavily with the THB-like domain to undergo critical conformation changes necessary for dimerization and ligand recognition. ^[2]

Epidermal Growth Factor-like Domain

The is very malleable and repositioning of this domain is essential for activation of the protein. This domain is able to undergo conformational changes with the ligand bound and when in contact with the TNF-like domain. The interface between the EGF-like and TNF-like domains are primarily hydrophobic residues, which enable their flexibility with regards to one another. The main motifs that are apart of the EGF-like domain are major and minor β-hairpins, which are stabilized by 3 conserved disulfide bridges. ^[2]

Binding Site

This site doesn't start out surrounding the ligand, instead the proximity of the ligand allows conformational changes across the protein. The ligands for ALK both have highly positively charged faces that interact with the TNF-like region, the primary ligand-binding site on the extracellular region^[3]. Salt bridges between the positively charged residues on the ligand and negatively charged residues on the receptor form are formed as the ligand approaches connecting the ligand with the receptor. Three of these occur between , , and . These strong ionic interactions allow the drastic conformational changes in the extracellular domain that induce the signaling pathway. ^[2]

Ligands

The extracellular ligands of ALK are ALKAL2 and ALKAL1.

ALKAL2

(Anaplastic Lymphoma Kinase Ligand 2) is a ligand of ALK as well as LTK located in the extracellular region. The full-length ALKAL2 (dimeric) and ALKAL2-AD (monomeric) can both induce dimerization of ALK ^[2]. Structurally, ALKAL2 has a N-termical variable region and a conserved augmentor domain and tends to aggregate in the cell ^[2]. Overexpression of ALKAL2 has been linked to high-risk neuroblastoma in absence of an ALK mutation ^[4] and could potentially have therapeutic opportunities.

ALKAL1

(Anaplastic Lymphoma Kinase Ligand 1) is a monomeric ligand of ALK, in addition to ALKAL2. Structurally, ALKAL1 and ALKAL2 contain an N-terminal variable region and a conversed C-terminal augmentor domain ^[2]. However, in ALKAL1, this N-terminal variable region is shorter, and shares no similar sequences to ALKAL2. Nevertheless, ALKAL1 shares a 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface which is used in ligand binding ^[2].

Dimerization of ALK

After binding to one of its ligands, ALK undergoes ^[1]. The dimerization causes trans-phosphorylation of specific tyrosine residues which in turn amplifies the signal. It has been presumed that the phosphorylation cascade activates ALK kinase activity ^[1].

Function

ALK plays a role in cellular communication and in the normal development and function of the nervous system It is present largely in the developing nervous system of a fetus and newborn, and overtime the expression of ALK dwindles with age. In addition to being expressed heavily in the brain, ALK has been shown to be present in the small intestine, testis, prostate, and colon ^[5].

Disease and Medical Relevance

Cancer

In ALK fusion proteins, the ALK fusion partner may cause dimerization independent of ligand binding, causing oncogenic ALK activation ^[1]. The regulation of ALK dimerization by ALKAL points to clear ways to inhibit ALK activity and may offer new therapeutic strategies in multiple disease settings ^[3]. Studies have shown that approximately 70-80% of all patients who have Anaplastic Large Cell Lymphoma (ALCL) contain the genetic complex of the ALK gene and the nucleolar phosphoprotein B23, also called numatrin (NPM) gene translocation, creating the NPM-ALK complex. This chimeric protein is expressed from the NPM promoter, leading to the overexpression of the ALK catalytic domain. This overexpression of ALK is characteristic of most cancers that are linked to tyrosine kinases, as the overexpression of these proteins leads to uncontrollable growth ^[5].

Pediatric Neuroblastoma

Mutations in ALK can produce oncogenic activity and are a leading factor in the development of some pediatric neuroblastoma cases^[4]. 8-10% of primary neuroblastoma patients are ALK positive^[4] suggesting that ALK overstimulation is a primary factor in propagating the growth of neuroblastoma. This overstimulation of ALK works in concert with the neural MYC oncogene, and uses the ALKAL2 ligand. Tyrosine kinase inhibitors are proposed to inhibit the growth of further neuroblastoma cells, creating a potential pathway of treatment^[4]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Huang H. Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces. Int J Mol Sci. 2018 Nov 2;19(11). pii: ijms19113448. doi: 10.3390/ijms19113448. PMID:30400214 doi:http://dx.doi.org/10.3390/ijms19113448
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 ^2.6 ^2.7 ^2.8 Reshetnyak AV, Rossi P, Myasnikov AG, Sowaileh M, Mohanty J, Nourse A, Miller DJ, Lax I, Schlessinger J, Kalodimos CG. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature. 2021 Dec;600(7887):153-157. doi: 10.1038/s41586-021-04140-8. Epub 2021, Nov 24. PMID:34819673 doi:http://dx.doi.org/10.1038/s41586-021-04140-8
↑ ^3.0 ^3.1 Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature. 2021 Dec;600(7887):148-152. doi: 10.1038/s41586-021-04141-7. Epub 2021, Nov 24. PMID:34819665 doi:http://dx.doi.org/10.1038/s41586-021-04141-7
↑ ^4.0 ^4.1 ^4.2 ^4.3 Borenas M, Umapathy G, Lai WY, Lind DE, Witek B, Guan J, Mendoza-Garcia P, Masudi T, Claeys A, Chuang TP, El Wakil A, Arefin B, Fransson S, Koster J, Johansson M, Gaarder J, Van den Eynden J, Hallberg B, Palmer RH. ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. EMBO J. 2021 Feb 1;40(3):e105784. doi: 10.15252/embj.2020105784. Epub 2021 Jan 7. PMID:33411331 doi:http://dx.doi.org/10.15252/embj.2020105784
↑ ^5.0 ^5.1 Della Corte CM, Viscardi G, Di Liello R, Fasano M, Martinelli E, Troiani T, Ciardiello F, Morgillo F. Role and targeting of anaplastic lymphoma kinase in cancer. Mol Cancer. 2018 Feb 19;17(1):30. doi: 10.1186/s12943-018-0776-2. PMID:29455642 doi:http://dx.doi.org/10.1186/s12943-018-0776-2

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1726"

@@ Line 8: / Line 8: @@
 === Domains ===
 ==== Three Helix Bundle-like Domain ====
-The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function overall as it interacts with the TNF-like domain upon ligand binding. The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain. This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding. The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" />
+The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function as it interacts with the TNF-like domain upon ligand binding. The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain. This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding. The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" />
 ==== Poly-Glycine Domain ====
 [[Image:glycinehelicesorange.png|300 px|right|thumb|Figure 2. Rare Glycine helices on Anaplastic Lymphoma Kinase]]Located between the THB-like domain and the TNF-like domain, the <scene name='90/904331/Polyg_region1/4'>Poly-Glycine Region</scene> has an important structural role. The GlyR domain also has a rare and unique structure of left-handed glycine helices with hexagonal hydrogen bonding shown in Figure 2. These 14 glycine helices are unique to ALK's function among other tyrosine kinases, as these types of structures on the binding domain are not present. These helices are rigid structures, providing a strong anchor for the ligand binding site while the other domains undergo drastic conformational rearrangements.<ref name="Reshetnyak" />
@@ Line 23: / Line 23: @@
 ==== ALKAL1 ====
 <scene name='90/904331/Alkal1/5'>ALKAL1</scene> (Anaplastic Lymphoma Kinase Ligand 1) is a monomeric ligand of ALK, in addition to ALKAL2. Structurally, ALKAL1 and ALKAL2 contain an N-terminal variable region and a conversed C-terminal augmentor domain <ref name="Reshetnyak" />. However, in ALKAL1, this N-terminal variable region is shorter, and shares no similar sequences to ALKAL2. Nevertheless, ALKAL1 shares a 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface which is used in ligand binding <ref name="Reshetnyak" />.
-=== Dimerization of Anaplastic Lymphoma Kinase ===
+=== Dimerization of ALK ===
 After binding to one of its ligands, ALK undergoes <scene name='90/904331/Alk_full_dimerization/3'>ligand-induced dimerization</scene> <ref name="Huang">PMID:30400214</ref>. The [https://en.wikipedia.org/wiki/Dimer_(chemistry) dimerization] causes trans-phosphorylation of specific [https://en.wikipedia.org/wiki/Tyrosine tyrosine] residues which in turn amplifies the signal. It has been presumed that the [https://en.wikipedia.org/wiki/Phosphorylation_cascade phosphorylation cascade] activates ALK kinase activity <ref name="Huang" />.
 == Function ==