Sandbox Reserved 1713

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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.

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Anaplastic Lymphoma Kinase

1 Introduction
2 Structure & Function
- 2.1 Conformational Change
- 2.2 Movement across the membrane
3 Disease
4 Relevance
5 Structural highlights

Introduction

Anaplastic Lymphoma Kinase is a receptor tyrosine kinase and is an integral membrane protein. ALK transfers a phosphate group from ATP to a tyrosine residue on an enzyme which activates a signaling cascade, and ALK becomes activated when a ligand called ALKAL binds to the binding surface on an extracellular domain of ALK.

Structure & Function

The extracellular portion of ALK has an inactive state, which is its monomerized form, and an active dimerized state with its ligands bound. The monomer is shown to the right in Figure 1, which has many different domains. The growth factor-like domain (EGF) connects the extracellular domains to the transmembrane domain (cyan). The tumor necrosis factor-like domain (TNFL) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand(orange). The glycine-rich domain (GlyR) contains 14 rare polyglycine helices that are hydrogen-bound to each other (green). The of these rare helices create a very rigid structure that is important for ALK function. The polyglycine extension loop (PXL) connects two of these polyglycine helices.

Figure 1

Figure 2

Conformational Change

In order for the Anaplastic Lymphoma Kinase (ALK) to move across the membrane to bind with the second monomer, it has to undergo a conformational change. The Anaplastic Lymphoma Kinase Activating Ligand (ALKAL) binds to the binding surface on the ALK. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward. ^[1] The kinase is now ready to move across the membrane and attach to the other kinase to be fully activated.

Movement across the membrane

The negatively charged phosphate groups on the cell membrane interact with the highly conserved positively charged residues on ALKAL ligand that face the membrane, which stabilizes the ligand to bind to ALK even better.

Disease

Relevance

Structural highlights

The active state of the kinase is when two monomers have completed a conformational change and moved across the membrane to form a .

References

↑ 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

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1713"

@@ Line 3: / Line 3: @@
 <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
 ==Introduction==
-Anaplastic Lymphoma Kinase is a receptor tyrosine [https://pubmed.ncbi.nlm.nih.gov/32114309/ kinase]. ALK transfers a phosphate group from [https://www.ncbi.nlm.nih.gov/books/NBK553175/ ATP] to a tyrosine residue on an enzyme which activates a signaling cascade, and ALK becomes activated when a ligand called [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789956/ ALKAL] binds to the binding surface on an extracellular domain of ALK. ALK is an integral membrane protein.
+Anaplastic Lymphoma Kinase is a receptor tyrosine [https://pubmed.ncbi.nlm.nih.gov/32114309/ kinase] and is an integral membrane protein. ALK transfers a phosphate group from [https://www.ncbi.nlm.nih.gov/books/NBK553175/ ATP] to a tyrosine residue on an enzyme which activates a signaling cascade, and ALK becomes activated when a ligand called [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789956/ ALKAL] binds to the binding surface on an extracellular domain of ALK.
-== Function ==
+== Structure & Function ==
+The extracellular portion of ALK has an inactive state, which is its monomerized form, and an active dimerized state with its ligands bound. The monomer is shown to the right in Figure 1, which has many different domains. The growth factor-like domain (EGF) connects the extracellular domains to the transmembrane domain (cyan). The tumor necrosis factor-like domain (TNFL) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand(orange). The glycine-rich domain (GlyR) contains 14 rare polyglycine helices that are hydrogen-bound to each other (green). The <scene name='90/904318/Glycinerichdomain/1'>hexagonal orientation</scene> of these rare helices create a very rigid structure that is important for ALK function. The polyglycine extension loop (PXL) connects two of these polyglycine helices.
 [[Image:Prote_ALK_Monomer_White.png|400 px|right|thumb|Figure 1]]
 [[Image:Proteo_ALK-ALKAL_Monomer_White.png|400 px|right|thumb|Figure 2]]
 <scene name='90/904318/Binding_surface_with_residues/3'>interacting residues of ALK and ALKAL</scene>
 <scene name='90/904318/Alk-alkal_binding_surface/2'>ALK-ALKAL binding surface</scene>
-<scene name='90/904318/Glycinerichdomain/1'>structure of the glycine-rich domain</scene>
 <scene name='90/904318/Alkalbindingsurfacewmembrane/1'>Binding surface of ALKAL with the membrane</scene>
 <scene name='90/904318/Alkal1membraneinteraction/2'>ALKAL's residues that interact with membrane</scene>

Sandbox Reserved 1713

From Proteopedia

Revision as of 02:39, 28 March 2022

Anaplastic Lymphoma Kinase

Contents

Introduction

Structure & Function

Conformational Change

Movement across the membrane

Disease

Relevance

Structural highlights

References

Views

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